The Science
Our work at YouthBio is rooted in the groundbreaking concept that aging is epigenetically controlled and potentially reversible. Pioneering research on cellular reprogramming using Yamanaka factors has demonstrated the reversibility of aging hallmarks at the cellular level. Our objective is to extend these results from the cellular level to the organismal level, optimizing the partial reprogramming approach for therapeutic use in a two-step gene therapy with a focus on tissue specificity.

Inspired by the landmark 2016 paper by Ocampo et al., we are working on a gene therapy that involves delivering genes responsible for epigenetic rejuvenation into target tissues. These genes would be inactive by default but can be periodically activated by a small molecule, rolling back the epigenetics of target tissues to a younger level and rejuvenating them. Our long-term vision is to apply this therapy systemically, decreasing patients' biological age and improving their health.

One important aspect of our therapies is their tissue specificity. From the start, we believed that partial reprogramming needs to be tissue-specific, as different organs have different reprogramming needs and tolerances, and some organs need to be avoided altogether, like the liver. Recently, Dr. Ocampo has confirmed that intuition as his lab has shown that avoiding the liver and intestine greatly expands the margin of safety of partial reprogramming, increasing the number of consecutive days of reprogramming that mice can fully tolerate from 4 to 10.

Numerous studies have provided strong evidence for the rejuvenating power of partial reprogramming, showcasing its potential in various contexts, such as improved muscle regeneration, heart regeneration, and intervertebral disc rejuvenation. The results of these studies serve as the foundation for our work at YouthBio.

Our work at YouthBio is rooted in the groundbreaking concept that aging is epigenetically controlled and potentially reversible. Pioneering research on cellular reprogramming using Yamanaka factors has demonstrated the reversibility of aging hallmarks at the cellular level. Our objective is to extend these results from the cellular level to the organismal level, optimizing the partial reprogramming approach for therapeutic use in a two-step gene therapy with a focus on tissue specificity.

Inspired by the landmark 2016 paper by Ocampo et al., we are working on a gene therapy that involves delivering genes responsible for epigenetic rejuvenation into target tissues. These genes would be inactive by default but can be periodically activated by a small molecule, rolling back the epigenetics of target tissues to a younger level and rejuvenating them. Our long-term vision is to apply this therapy systemically, decreasing patients' biological age and improving their health.

One important aspect of our therapies is their tissue specificity. From the start, we believed that partial reprogramming needs to be tissue-specific, as different organs have different reprogramming needs and tolerances, and some organs need to be avoided altogether, like the liver. Recently, Dr. Ocampo has confirmed that intuition as his lab has shown that avoiding the liver and intestine greatly expands the margin of safety of partial reprogramming, increasing the number of consecutive days of reprogramming that mice can fully tolerate from 4 to 10.

Numerous studies have provided strong evidence for the rejuvenating power of partial reprogramming, showcasing its potential in various contexts, such as improved muscle regeneration, heart regeneration, and intervertebral disc rejuvenation. The results of these studies serve as the foundation for our work at YouthBio.
Key Scientific Publications:

  1. In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming (Ocampo et al. 2016): Demonstrated that partial reprogramming with Yamanaka factors can extend lifespan by up to 50% in progeric mice and improve aging phenotypes in some tissues of regular, non-progeric mice.
  2. Reprogramming to recover youthful epigenetic information and restore vision (Lu et al. 2020): Showed that expression of Oct4, Sox2, and Klf4 genes (OSK) in mice promotes more youthful gene expression patterns and restores vision in a mouse model of glaucoma.
  3. Transient non-integrative nuclear reprogramming promotes multifaceted reversal of aging in human cells (Sarkar et al. 2020): Demonstrated that partial reprogramming via transient expression of mRNAs reverses cellular aging and epigenetic clock in human fibroblasts, endothelial cells, and chondrocytes without abolishing cellular identity.
  4. Gene Therapy Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice (Macip et al.): Demonstrated that using partial reprogramming by OSK factors in 124-week-old wild type (non-progeric) mice extended median remaining lifespan by 109% and improved health parameters, including frailty scores, indicating an enhancement in both healthspan and lifespan.
  5. A single short reprogramming early in life improves fitness and increases lifespan in old age (Alle et al. 2021): Found that a single partial reprogramming course early in life improves body composition and functional capacities over the entire lifespan in mice.
  6. In vivo reprogramming leads to premature death due to hepatic and intestinal failure (Parras et al. 2022): Showed that the liver and intestine are the two key tissues that can cause premature death from reprogramming, and avoiding them extends the duration of consecutive days of OSKM reprogramming that mice can fully tolerate from 4 to 10 days.
  7. Multi-omic rejuvenation of human cells by maturation phase transient reprogramming (Gill et al. 2022): Showed that it is possible to separate rejuvenation from pluripotency reprogramming, opening the door to the possibility of discovering novel anti-aging genes and therapies.
  8. Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice (Chen et al. 2021): "In this study, we demonstrate that heart-specific expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) induces adult CMs to dedifferentiate, conferring regenerative capacity to adult hearts. … Short-term OSKM expression before and during myocardial infarction ameliorates myocardial damage and improves cardiac function, demonstrating that temporally controlled dedifferentiation and reprogramming enable cell cycle reentry of mammalian CMs and facilitate heart regeneration."
  9. Reduction of Fibrosis and Scar Formation by Partial Reprogramming In Vivo (Doeser et al. 2018): "These data provide proof of concept that OSKM-mediated partial reprogramming in situ can diminish fibrosis and improve tissue healing with less scar formation without the risk of tumor formation."
  10. In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice (Browder et al. 2022): "Long-term partial reprogramming lead to rejuvenating effects in different tissues, such as the kidney and skin, and at the organismal level; duration of the treatment determined the extent of the beneficial effects. The rejuvenating effects were associated with a reversion of the epigenetic clock and metabolic and transcriptomic changes, including reduced expression of genes involved in the inflammation, senescence and stress response pathways. Overall, our observations indicate that partial reprogramming protocols can be designed to be safe and effective in preventing age-related physiological changes."
  11. In Situ Pluripotency Factor Expression Promotes Functional Recovery From Cerebral Ischemia (Seo et al. 2016): Found that transient expression of OSKM in a mouse model of cerebral ischemia promoted the generation of astrocytes and neural progenitors, increased neovascularization, and provided neuroprotective effects. Importantly, this treatment led to significant functional restoration from ischemic injury without tumor development, suggesting that partial reprogramming can be beneficial as a treatment for cerebral ischemia.
  12. In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche (Wang et al. 2021): "[We] demonstrate that local expression of OSKM, specifically in myofibers, induces the activation of muscle stem cells or satellite cells (SCs), which accelerates muscle regeneration in young mice. In contrast, expressing OSKM directly in SCs does not improve muscle regeneration. … Thus, short-term induction of the Yamanaka factors in myofibers may promote tissue regeneration by modifying the stem cell niche."
  13. Partial reprogramming strategy for intervertebral disc rejuvenation by activating energy switch
    (Cheng et al. 2022): "partial reprogramming through short-term cyclic expression of Oct-3/4, Sox2, Klf4, and c-Myc (OSKM) inhibits progression of [intervertebral disc degeneration], and significantly reduces senescence related phenotypes in aging NPCs. Mechanistically, short-term induction of OSKM in aging NPCs activates energy metabolism as a "energy switch" by upregulating expression of Hexokinase 2 (HK2) ultimately promoting redistribution of cytoskeleton and restoring the aging state in aging NPCs."
  14. Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming (Chondronasiou et al. 2022): Found that this single period of OSKM expression was sufficient to reverse age-related changes in DNA methylation, transcription, and metabolites in multiple tissues (pancreas, liver, spleen, and blood) and serum in aged mice. This indicates that a single cycle of transient reprogramming can effectively drive epigenetic, transcriptomic, and metabolomic changes towards a more youthful state in various tissues.