Cellular Partial Reprogramming for Human Longevity: Industry Readiness and Pipeline Overview

ChatGPT has focused the world’s attention on AI, while OpenAI CEO Sam Altman is also focusing on another area of research: extending human lifespan through cellular reprogramming. His $180 million investment in Retro Biosciences was recently disclosed to the public. In addition, Altos Labs, which has secured $3 billion in funding, and NewLimit, a biotechnology company founded by billionaire Brian Armstrong, share similar visions.Partial Reprogramming Is the Hottest Topic in Current Longevity Research, this field has become one of the most well-capitalized areas of research.

In 2006, Professor Shinya Yamanaka discovered four transcription factors (Oct4, Sox2, Klf4, and C-Myc) that can revert mature cells back to stem cells, a process known as reprogramming. Reprogramming produces two effects:

1) Dedifferentiation (converting differentiated cells into stem cells),

2) Rejuvenation (making cells younger).

Can we achieve rejuvenation without undergoing dedifferentiation? In 2010, Prim Singh proposed that instead of applying Yamanaka factors “fully,” they could be applied “partially.”Revitalizing Cells Without Inducing Dedifferentiation. This marks the birth of partial reprogramming.

Until 2016, this theory achieved success in mice: researchers such as Ocampo extended the median lifespan of progeria-afflicted mice by 33%–50% through partial reprogramming. Meanwhile, based on studies by Roux, Olova, and others in animal and human cells, it was found that dedifferentiation and rejuvenation do not exhibit a strong correlation. This discovery suggests a potential approach to decouple these two processes, thereby transforming partial reprogramming into a viable therapeutic strategy.

Partial reprogramming, in its traditional sense, refers to the partial application of Yamanaka factors to cells, with the aim of restoring cellular vitality without altering their identity. As industry and academic research have deepened, the meaning and applications of this concept have evolved through the incorporation of regulatory factors beyond the Yamanaka factors and the expansion into diverse application scenarios. Consequently, the scope of research and applications in the field of partial reprogramming has been further extended, while the terminology used to describe it has gradually shifted, with terms such as “Rejuvenation” or “Revitalization” increasingly being adopted.

Cellular reprogramming is primarily achieved through two approaches:

1) Delivery of Exogenous Transcription Factor Systems into Cells or AnimalsFor instance, desired functionalities can be delivered by packaging cell-fate transcription factors into viral vectors or mRNA and subsequently introducing them into cells or animals. Beyond academic research, this technological approach has been adopted by several startups, such as YouthBio and Altos Labs.

2) Activation or modulation of endogenous fate transcription factor expression. Most cells already possess endogenous fate-determining transcription factors; what is required is the activation or regulation of the expression of these endogenous fate-control factors. For instance, small-molecule combinations can be used to influence or regulate the expression of endogenous cell fate regulators, thereby achieving the desired functional outcomes. Representative companies adopting this approach include Retro Biosciences and Xinrui Regenerative Medicine.

This field is relatively new, with approximately 19 related articles published (see Appendix for details).

Before fully understanding the true meaning of aging, current research primarily evaluates it from three aspects: transcriptomics, hallmarks of aging, and epigenetic clocks. Among these, the indicators for measuring rejuvenation are: extended lifespan, physiological improvements, and improvements in molecular biomarkers.

Overall, transcriptomic analysis is more standardized and systematic than observing specific aging markers, thereby enabling a more comprehensive assessment through the transcriptome. The method for determining whether a cell is rejuvenating involves examining the expression of all genes within the cell, i.e., its transcriptome. Transcriptomic studies generally include the following steps:

a) Obtain the transcriptomes of young and aged cells;

b) Obtain the transcriptome of aged cells that have undergone partial reprogramming;

c) Use statistical analysis to compare the transcriptomes of young cells, untreated aged cells, and treated aged cells to assess the extent to which the treatment “rejuvenates” the cells.

These analyses include: Principal Component Analysis (PCA): This analytical approach allows us to visualize how the overall phenotypic data cluster together following these interventions. If treated aged cells are closer to young cells than untreated aged cells, this suggests that the treatment partially “restores” the vitality of aged cells in these samples. Some studies have even developed unique transcriptomic age scores (Gill 2021, Roux 2021).

In the past, due to technological and cost constraints, establishing practical high-throughput transcriptome analysis was no easy feat; nevertheless, numerous researchers and enterprises both internationally and in China have made significant efforts in this direction. It is reported that, leveraging the principles of single-cell sequencing and their substantial technical expertise, some pioneering companies have overcome major obstacles, thereby greatly enhancing the accessibility of this technology.

In general,Partial Reprogramming Extends Lifespan in LAKI Mice, a Progeria Mouse Model, meanwhile, the scientific community believes that partial reprogramming can not only treat progeria but also influence aging, for the following reasons:

1) First, progeria is caused by mutations in the Lamin A protein, and the accumulation of the mutated protein, which subsequently impairs cellular function, is the primary cause of premature aging in LAKI mice. However,Partial reprogramming does not alter the expression or accumulation of mutant Lamin A protein. Therefore, the extended lifespan of LAKI mice after treatment is most likely a result of improvements in other aging processes;

2) Secondly,Partial reprogramming indeed leads to systemic improvement of aging-related biomarkers in wild-type mice and human cells., particularly improvements in age-related functions (e.g., vision, cardiac function, and glucose tolerance).

Research on Partial Reprogramming in Different Types of Tissues

The y-axis represents the number of relevant studies.

Overall, partial reprogramming is a promising regenerative intervention that can be applied to various organs and tissues. Although it is still in its early stages, it targets an (arguably universal) aging process.

Currently, partial reprogramming has demonstrated rejuvenating effects in both mouse and human cells for skin and muscle tissues. These findings have been consistently replicated across multiple studies within the same species, leading many companies with partial reprogramming pipelines to include skin-related applications.

In the field of disease treatment, research has primarily focused on the rejuvenation effects in specific tissues and organs, rather than systemic rejuvenation. Representative studies include Lu et al., 2020; Chen et al., 2021; Sarkar et al., 2020; and Wang et al., 2021.

They investigated the regenerative effects of partial reprogramming on retinal ganglion cells, cardiomyocytes (heart cells), and muscle stem cells using distinct protocols. In brief, partial reprogramming was able to induce functional improvements in all these cell types. These benefits included enhanced visual function and regenerative capacity of retinal ganglion cells (RGCs) after injury, as well as improved regenerative potential of both cardiac tissue following heart injury and muscle stem cells after damage.

Based on extensive animal studies, partial reprogramming has initially demonstrated the effects and potential of restoring vitality. Overall, the effects of partial reprogramming are also applicable to human cells, and in vitro testing has currently been conducted in five important types of human cells (muscle stem cells, neurons, chondrocytes, endothelial cells, and fibroblasts). Among these, therapeutic potential has been shown for human muscle stem cells and neurons, while a vitality-restoring effect has been observed in human chondrocytes, endothelial cells, and fibroblasts.

Currently, most protocols involve processing times of less than four days; perhaps longer-term experiments across different human cell types would yield more evidence.

Partial reprogramming, sometimes referred to as epigenetic reprogramming, involves substantial changes in the cell’s epigenetic state during the reprogramming process, which may facilitate regeneration. This has been confirmed by studies that observed attenuated regenerative effects when epigenetic changes were interrupted during partial reprogramming.

This mechanism also suggests the potential to identify other factors capable of regulating cell fate beyond OSKM. For instance, Wang et al. (2021) discovered that Wnt4 is a key downstream factor driving the regenerative capacity of muscle stem cells after partial reprogramming; therefore, further research may uncover novel factors that act downstream of OSKM.

Comprehensive screening will be a crucial approach for discovering and identifying new factors beyond OSKM, with promising efforts both domestically and internationally. For instance, through genome-wide CRISPR screening, Shift Therapeutics identified 50 novel reprogramming factors. Leveraging its proprietary high-throughput transcriptomic screening platform, Xinrui Regenerative Medicine has also discovered candidate small molecules capable of inducing partial cellular reprogramming and reversing disease phenotypes in multiple therapeutic areas.

With the rapid advancement of cell reprogramming technologies and their applications, an increasing number of companies are now employing cell reprogramming approaches to treat related diseases, aiming to rejuvenate tissues, organs, and even the entire human body. Notable examples include Retro Bio, Altos Labs, Turn Biotechnologies, YouthBio Therapeutics, NewLimit, Shift Bioscience, and Xinrui Regenerative Medicine. In addition, Calico, launched by Google in 2013, has also begun to focus on cell reprogramming.

In general, the core approaches of relevant companies can be divided into two categories:

1）Partial reprogramming using OSKM and related combinations, such as using only OSK or different induction methods.；

2） Reprogramming Using Novel Transcription Factors or Small Molecules as Alternatives to OSKM。

Progress and Technical Features of Reprogramming Companies

Retro Biosciences

Established in early 2021, their goal is to identify alternative factors beyond OSKM for achieving cellular rejuvenation, with a primary focus on “single-cell multi-omics and machine learning-based computational biology.”

Altos Labs

Founded in mid-2021, it has assembled an impressive roster of scientific luminaries with $3 billion in funding. This represents the largest single amount of capital dedicated to reprogramming to date.

Beyond combating aging, Altos Labs’ corporate mission points to an even more ambitious goal: reversing diseases, injuries, and disabilities that may occur at any stage of life through cellular rejuvenation reprogramming.

Xinrui Regeneration

Founded in 2019, the company’s founding team and core members hail from prestigious universities such as Peking University, Tsinghua University, Fudan University, the Hong Kong University of Science and Technology, and the California Institute of Technology.

Headquartered in Nanjing, this innovative drug R&D company is founded on the principles of cell fate remodeling and regeneration. Leveraging its proprietary “Cell Rejuvenation” drug discovery platform, the company is dedicated to developing novel therapeutics based on mechanisms such as in situ tissue and organ regeneration, fibrosis reversal, and tumor cell reprogramming. Its core technologies include high-throughput targeted transcriptome sequencing, cell imaging-based machine learning, advanced techniques for iPS cell differentiation and primary cell culture, sophisticated small-molecule target and mechanism of action (MOA) elucidation, and computational chemistry.

Partial reprogramming, a technology with immense potential, is experiencing explosive growth due to the revolutionary medical benefits of rejuvenating or renewing human tissues. Although the number of related startups both in China and abroad remains limited due to technical barriers, given the current trajectory of biotechnological development, the rapid pace of new discoveries in this field, and the volume of capital flowing into it,The coming years are likely to witness sustained robust prosperity.

References

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