For millennia humans have searched for ways to delay ageing, from the ancient Greeks using honey and yogurt as skincare to today’s elaborate cosmetic procedures. But what if there was a way to truly reverse ageing at a cellular level? Two research teams have successfully reversed signs of ageing in mice – the question remains if this could be replicated in humans.
In 2012, Kyoto University biologist Shinya Yamanaka won a share of a Nobel Prize for discovering how mature cells in mice could be reprogrammed to become immature stem cells. He found that by introducing a few genes, so-called ‘Yamanaka factors’, he could reprogram mature cells to become pluripotent stem cells: immature cells which are able to develop into all types of body cells. A decade on, two teams argue that these genes could turn back the clock for entire organisms.
To explore Yamanaka factors as a therapy that might one day lead to practical treatment for humans, San Diego-based biotech company Rejuvenate Bio injected elderly (124-week-old) mice with adeno-associated viruses (AAVs) carrying genes for three Yamanaka factors (collectively known as OSK). The company reported that the treated mice lived another 18 weeks on average: double the 9 weeks of the control group, and 7% longer overall. The treatment also reportedly resulted in partial recovery of DNA methylation patterns. This result may suggest that one day older people could turn back their biological clocks with an injection – literally becoming younger.
This reprogramming technique, which involves resetting cells to a ‘younger’ state, has sparked major interest among investors and the scientific community alike – with hundreds of millions being invested into this potential elixir of youth. The paper by Rejuvenate Bio could represent widely anticipated proof that this method could indeed extend animal lives, but it remains to be seen if this is a viable treatment for humans. Although some studies have suggested Yamanaka factors could increase the chances of developing cancer, Noah Davidsohn, Rejuvenate’s chief scientific officer and co-founder, says they have seen no obvious negative effects to date.
A second study demonstrates for the first time that a breakdown in the way DNA is organised and regulated can drive ageing in an organism, independent of changes to the genetic code itself. This ageing happens as a result of epigenetic changes, which means rather than the genetic code itself being changed, the expression of that code is changed. The study was released by a team led by David Sinclair, a Harvard Medical School professor of genetics known for having previously backed several ‘anti-ageing’ interventions, such as the use of resveratrol, causing controversy in the scientific community.
Sinclair aimed to demonstrate that loss of epigenetic information can drive ageing, and that its restoration can reverse it. This would prove his ‘information theory of ageing’, which proposes that imperfections in cells’ DNA-repairing mechanisms can lead to degradation over time. This cumulative loss of epigenetic markers leads to our bodies getting old.
To test his theory, the team genetically engineered mice to introduce breaks in their DNA at 20 sites in the genome. The animal’s cells repaired the damage, but widespread changes in DNA methylation patterns and gene expression followed, consistent with Sinclair’s theory. This resulted in the mice having epigenetic signatures similar to those of much older animals, and within weeks they showed signs of frailty and tissue ageing, including hair and pigment loss in addition to health deterioration.
To see whether this epigenetic degradation was reversible, the Harvard group, similarly to Rejuvenate, injected the ‘aged’ mice with adeno-associated viruses carrying OSK Yamanaka factors. Analyses of the mice’s kidneys, retinas and muscles demonstrated that this did indeed reverse some of the epigenetic changes induced by the DNA breaks.
Peers within the scientific community have both praised and critiqued the findings of the two groups, with molecular biologists warning that the Harvard team’s indirect process of inducing epigenetic changes using dramatic DNA breaks makes it hard to prove which changes are causing ageing, positing that the DNA breaks could be impacting ageing through a different route. Jan Vijg, a geneticist at the Albert Einstein College of Medicine, highlights that it is unclear how well mice with induced DNA breaks mimic naturally aged animals. He stresses that ageing is a complex process with a wide range of contributing factors. Vijg emphasises that in both these studies, the effect of treatment with OSK factors was moderate at best: a minor extension of lifespan in one and a partial reversal of artificially induced ageing symptoms in the other. The idea that ageing can now be wound backwards is not yet justified by research, Vijg cautions.
Despite criticism, both groups are looking to move their work toward the clinic, with Rejuvenate examining the mechanisms underlying its treatment’s action and tweaking its delivery. Sinclair says his team is already testing AAV-delivered OSK in the eyes of monkeys: “If those studies in monkeys go well and everything looks safe enough for humans, the plan is to immediately apply to the FDA [Food and Drug Administration] to do a study in one or more [age-related] diseases of blindness,” he told the American Association for the Advancement of Science.
We have already seen gene and cell therapy move from the realm of science fiction to medical reality. We still have a long way to go, but these studies could be laying the foundations for yet another revolution in the rapidly developing field of genetic medicine.
