Preclinical study investigates neuron-targeted partial cellular reprogramming in the hippocampus to mitigate age-related cognitive impairments.
A preprint study led by Dr Alejandro Ocampo, in collaboration with YouthBio Therapeutics, has yielded some interesting insights into the potential of neuron-specific partial reprogramming as a therapeutic intervention for age-related cognitive decline. The research, although not yet peer-reviewed, represents a significant step forward in the exploration of partial cellular reprogramming – a technique that, in contrast to full cellular reprogramming, aims to rejuvenate cells without erasing their identity.
Longevity.Technology: Cellular reprogramming, a process that involves resetting the epigenetic marks of a cell to return it to a more youthful state, has been the focus of significant attention since its inception. This technique, often achieved through the induction of Yamanaka factors (OSKM: Oct4, Sox2, Klf4 and c-Myc), has the potential to reverse age-associated phenotypes, but it is not the Holy Grail it is often touted to be, as full reprogramming poses serious risks, including loss of cell identity and organ failure. Enter partial reprogramming, which, by contrast, employs cyclic or tissue-specific expression of these factors, potentially offering a safer method to rejuvenate tissues while preserving their functional roles.
The implications of such an approach for extending healthspan – if not lifespan – are huge. By targeting specific tissues or cell types, researchers aim to mitigate the detrimental effects of aging without the risks associated with full cellular reprogramming, and this in turn could open new avenues for treating age-related diseases.
Neuron-specific reprogramming
The study focused on the dentate gyrus, a region within the hippocampus known for its role in memory and learning. The researchers employed two distinct approaches: a transgenic mouse model designed for neuron-specific reprogramming and a targeted lentiviral delivery system for OSKM factors. The goal was to explore whether partial reprogramming could ameliorate cognitive decline in aging mice without disrupting the essential functions of mature neurons.
And the results were promising – aged mice subjected to neuron-specific partial reprogramming exhibited significant improvements in learning and memory, particularly those treated with lentiviral OSKM delivery to the dentate gyrus. This effect was not observed in younger mice, suggesting that the benefits of partial reprogramming may be more pronounced in older subjects with established age-related cognitive decline [1].
“These exciting findings from our collaboration with Dr Ocampo validate our approach and highlight the transformative potential of partial reprogramming in combating age-related cognitive decline,” said Yuri Deigin, CEO of YouthBio.
Ocampo further emphasized the potential of tissue-specific reprogramming, particularly in neurodegenerative conditions, noting: “I believe that once we fully understand how to use this approach in a tissue-specific manner – something that YouthBio has recognized since the company’s inception – we will see even greater increases in lifespan and more beneficial therapeutic effects in various disease models.”
Implications for neurodegenerative disease therapies
Beyond cognitive decline associated with normal aging, the study also raises the possibility that partial reprogramming could be leveraged to treat neurodegenerative conditions such as Alzheimer’s disease. In a related study, YouthBio reported that transgenic mice treated with inducible OSKM vectors exhibited reduced amyloid-beta levels and improved cognitive performance, supporting the broader therapeutic potential of this approach.
“The potential of partial reprogramming for brain rejuvenation and the treatment of neurodegenerative disorders is very promising,” said João Pedro de Magalhães, PhD, Chief Scientific Officer of YouthBio. “Our recent findings suggest that partial reprogramming could play a significant role in addressing age-related cognitive decline. While there is still much to learn and refine, these early results are encouraging and provide a solid foundation for further research. We are cautiously optimistic that with continued investigation, we can develop effective therapies that may one day benefit patients suffering from conditions like Alzheimer’s disease.”
YouthBio’s commitment to advancing this technology toward clinical applications is evident; the company aims to initiate clinical trials for its Alzheimer’s therapy within three years. In parallel, it continues to explore the broader potential of partial reprogramming, including its applicability to other neurodegenerative disorders and age-related diseases.
Straight from the (sea)horse’s mouth
Longevity.Technology spoke to Yuri Deigin, CEO of YouthBio, about the results, and he told us his company has been focused on the brain from the very beginning, as the team believe it is the most important organ for human aging.
Yuri Deigin is CEO of YouthBio Therapeutics
“While our ultimate goal is a comprehensive therapy that can rejuvenate all critical organs, it made sense to start with the brain, not in small part due to the significant unmet clinical need in neurodegenerative disorders,” he said.
Deigin explained that YouthBio realized very early on that partial reprogramming needs to be tissue-specific.
“Some cell types are too permissive to reprogramming, which can lead to organ failure. This was beautifully demonstrated by Professor Ocampo in 2023, where he showed that by avoiding only the liver and the intestine, the safety margin of partial reprogramming can be significantly increased from 4 to 10 days of consecutive OSKM expression.”
The brain is also a good target because neurons provide a significant safety margin for partial reprogramming, Deigin explains, as neurons can be pushed them quite far while still maintaining their cellular identity and function.
“This was demonstrated recently by Horvath et al. in their paper, where they used brain-specific OSKM induction in old rats and observed beneficial effects on their cognitive function.”
Deigin is also encouraged by the increasing evidence of the therapeutic benefits of partial reprogramming in neurodegenerative conditions like Alzheimer’s, citing work by Altos Labs and its collaborators that demonstrates the therapeutic potential of brain-specific partial reprogramming in preventing Alzheimer’s symptoms.
“At YouthBio, Alzheimer’s is our primary indication and we have also observed positive effects in an Alzheimer’s mouse model using our brain-specific partial reprogramming therapies, and so our next goal is to take our Alzheimer’s therapy to the clinic.”
Future directions… and potential challenges
While the study presents an encouraging outlook on the therapeutic potential of partial reprogramming, there are challenges ahead; the precise mechanisms by which partial reprogramming ameliorates cognitive decline are not yet fully understood, and long-term safety studies are essential to ensure that this approach does not lead to adverse effects, such as oncogenesis or unintended cellular changes.
Also, as is always the way, the translation of these findings from mouse models to human applications will require extensive validation and refinement. Nevertheless, the current research provides a promising foundation for future studies and we look forward to the publication of the peer reviewed results.
