Exciting research just released by Rejuvenate Bio shows how a subset of Yamanaka factors resulted in a doubling of life remaining in old mice (equivalent to 83 year old humans) and living that time in a healthier state.
The aim of the study was to see whether Yamanaka factors are capable of extending the lifespan of aged wild type mice, i.e. naturally aged, not mice bred to age rapidly (progeroid) which may show improvement but only back to normal ageing.
Background
Back in 2006, Shinya Yamanaka showed that introducing four specific genes (Myc, Oct3/4, Sox2 and Klf4 - now referred to as “Yamanaka factors”) to differentiated cells, it was possible to generate pluripotent stem cells (which can divide and different types of cells).
Since then, researchers have been playing with different subsets and variations of these factors, and also applying them for less time than it takes for the cell to convert to a stem cell. What has been observed is that halfway through the reversal process, the cells revert to a more youthful state; so stopping at that point means the cells retain their identity (as whatever type of cell they started out as).
Study Method
The team from Rejuvenate Bio, led by its CSO and co-founder Noah Davidsohn, used only the OSK factors, delivering the genes using adeno-associated viruses (AAV) which is a standard gene therapy technique of getting the required genes inside cells. The treatment also required the consumption of doxycycline (an antibiotic) to trigger the action.
The treatment started when the mice were 124 weeks old and half of them had already died. This, by definition, is life expectancy, so is the equivalent of being 83 years old in humans. The OSK expression was then induced on alternate weeks for the remainder of the animals’ lives.
The control mice were only given doxycycline, and their survival curve closely followed that of standard Jax labs mice, confirming that doxycycline alone had no adverse nor advantageous effects.
As an addendum, the therapy was also tested on human cells (in vitro) using skin cells taken from the scalp of a 65-year-old male.
Results
After treatment started, the control mice lived for a further 8.86 weeks on average (i.e. until half of those had died) whilst the treated mice survived 18.5 weeks – a 109% increase in remaining life expectancy. A human who reaches 83 years old in the UK lives about 8 years more (on average, i.e. remaining life expectancy), so this result is the equivalent of treating 83 year olds and increasing their life expectancy from 91 to 99 years.
IMAGE - Survival curve
A common objection to life extension is that it would be more years in decrepitude, understandably as who wants to live longer in pain and isolation, however, the treated mice were 20% less frail than the control ones, based on a 28 point frailty index (FI) that included physical and physiological observations as well assimple sensorial and motor tests.
Also, importantly, no gross teratoma formation was observed.
Finally, In the human cells (in a dish), the treated cells experienced significant epigenetic age reversal.
Given the increase in lifespan, the reduction in frailty, and the age reversal in human cells, these results imply that intermittent cellular reprogramming could be translated into a therapeutic that increases lifespan and healthspan in humans.
Reference
Gene Therapy Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice – Noah Davidsohn et al - bioRxiv 2023
Note: this research has been published in a preprint server, which means it has not been peer reviewed yet. However, the company was co-founded by George Church, so the team would be putting theirs, his and the company’s reputation at risk if they were reporting anything obviously erroneous.
