Highlights: 

  • A gene therapy injected directly into the brain prevents learning impairments in aged rats. 
  • The gene therapy delivers genes called Yamanaka factors, which cause cells to revert to an earlier stage of development, making them appear younger. 
  • Cancer, previously shown to be induced by Yamanaka genes, was not detected in this study. 

Renowned Harvard professor David Sinclair and other scientists have seemingly discovered the secret to triggering youth stagnation. However, many unanswered questions remain and much work is needed before this feat can be achieved in humans. 

One question is whether a set of genes called Yamanaka factors can counteract the decline in learning and memory that comes with age. To answer this question, Californian and Argentinian scientists have employed Sinclair’s method to rejuvenate the cognitive abilities of aged rats. 

The method, a gene therapy that delivers Yamanaka genes, was shown to significantly improve the learning capacity of aged rats. This was determined by placing young or aged rats in the center of a circular platform with 20 holes surrounding the edge. Of the 20 holes, one led to an escape box. Throughout six training sessions, the researchers measured how long it took the rats to find the escape box after startling them with a bright light and high-pitched noise. 


(Image: scantox.com) Escaping Barnes Maze. A mouse searching for the hole with an escape box in the Barnes Maze test, used to assess rodent learning and memory.

Where young rats quickly learned to find the escape box over the course of six training sessions, aged rats seemed not to learn. By the sixth session, the aged rats took nearly 1 minute and 40 seconds to find the escape box while the young rats took only 30 seconds. However, the researchers discovered that learning impairments could be prevented. Namely, the aged rats that received the Yamanaka gene therapy took about 1 minute to find the escape box on the sixth session, suggesting the gene therapy mitigates age-related deficits in learning.

(Hovarth et al., 2024) Yamanaka Gene Therapy Counteracts Age-Related Learning Impairments. Over six trials, young rats (white, Young) greatly reduced their escape time (Latency to escape box) from about 90 seconds (s) for acquisition trial 1 (AT1) to 30 seconds for AT6. In contrast, normal old rats (black, Old Control) hardly improved. However, by the fifth (AT5) and sixth session (AT6), old rats treated with the Yamanaka gene therapy (gray, Old OSKM) found the escape box faster than normal old rats.

Subsequently, to assess spatial memory, the researchers removed the escape box. They then measured how long the rats explored the hole where the escape box was formerly located. It was presumed that the longer the time spent exploring the correct hole, the better the spatial memory of the rats. While the gene therapy modestly improved correct-hole exploration time, this was not significant. Thus, these results suggest that the Yamanaka gene therapy improves learning but not necessarily spatial memory. 

Yamanaka Gene Therapy 

Yamanaka factors are a set of four genes, abbreviated OSKM (OCT4, SOX2, KLF4, and MYC). Yamanaka genes are used to induce cellular reprogramming, which essentially makes cells younger, as shown by a study that made human skin cells 30 years younger. When delivered using gene therapy, the Yamanaka genes extend the remaining lifespan of mice by 109%. Furthermore, Yamanaka gene therapy has been shown to restore the vision of primates.

The California- and Argentina-based researchers administered the Yamanaka genes via direct injections into the hippocampus of aged rats. The hippocampus is a region of the brain important for learning and memory formation. Notably, the researchers previously showed that injecting Yamanaka genes into another region of the brain called the hypothalamus improves the fertility of female rats. Still, more studies will be needed to determine how Yamanaka gene therapy could be delivered to human brain tissue without surgery. 

Good News: No Cancer 

Previous studies have shown that Yamanaka genes can lead to the development of cancer. Cancerous growths are a primary worry when it comes to administering Yamanaka genes as a longevity therapy. This is considering that Shinya Yamanaka won the Nobel prize in physiology and medicine for converting non-stem cells into stem cells using what are now called Yamanaka genes, or Yamanaka factors. 

The California-based researchers, including Steve Horvath, professor at the University of California Los Angeles and principal investigator at Altos Labs in San Diego, and Argentina-based researchers, including Rodolfo G. Goya, a researcher at the University of La Plata, did not find any signs of cancer or any other adverse effects after 39 days of Yamanaka gene therapy. The authors say, 

“Given the inherent rejuvenating properties of the Yamanaka genes, studies examining their functional effects in adult and old animals present a promising research avenue in regenerative medicine.”