Aging is driven by cumulative molecular damage and epigenetic changes that disrupt cellular function, but recent advances in partial cellular reprogramming suggest that this process may be reversible. OKSM (Oct4, Sox2, Klf4, and c-Myc) transcription factors have demonstrated the ability to reset epigenetic markers, restoring youthful gene expression and improving cellular function without erasing cell identity. Studies in animal models and human cells have shown that transient OKSM expression can rejuvenate tissues, extend lifespan, and potentially treat age-related diseases like neurodegeneration and cardiovascular decline. However, challenges remain in controlling reprogramming efficiency, mitigating oncogenic risks, and developing safe delivery methods for clinical translation.
Aging is an intricate biological process characterized by the gradual deterioration of cellular function, leading to increased vulnerability to diseases and ultimately death. Throughout history, scientists and physicians have sought ways to slow or reverse this decline, from early alchemical pursuits of an “elixir of life” to modern regenerative medicine techniques. In recent decades, advances in cellular and molecular biology have shifted the focus from external interventions, such as pharmaceuticals and dietary modifications, to reprogramming cells at a fundamental level. Among the most promising breakthroughs in this field is the discovery that aging may be epigenetically reversible, with transient cellular reprogramming offering a pathway to restore youthful function without the risks associated with full dedifferentiation.
A pivotal moment in this field came in 2006 when Shinya Yamanaka identified a set of four transcription factors — Oct4, Sox2, Klf4, and c-Myc (OKSM) — that could convert differentiated adult cells into a pluripotent state resembling embryonic stem cell.1 This discovery, which earned Yamanaka the Nobel Prize in 2012, demonstrated that cell fate is not fixed, but rather dictated by reversible epigenetic modifications. The introduction of these transcription factors erases the epigenetic markers that distinguish a specialized cell, such as a neuron or skin fibroblast, resetting it to a stem-cell-like state. This finding sparked immense interest in regenerative medicine, as it suggested that tissues damaged by aging or disease could be rejuvenated or even regenerated.
However, the full reprogramming of cells into induced pluripotent stem cells (iPSCs) presents significant risks. Once a cell reverts to pluripotency, it loses its original identity and function, posing challenges for controlled differentiation back into specialized cell types.2 Moreover, the process can induce genomic instability and an increased likelihood of tumor formation, largely due to the oncogenic properties of c-Myc.3 These concerns limit the clinical application of full cellular reprogramming.
To address these challenges, researchers have explored partial cellular reprogramming, in which the Yamanaka factors are expressed transiently or in a controlled manner to rejuvenate cells without causing complete dedifferentiation. This strategy aims to reset key epigenetic markers of aging while preserving the cell’s original identity and function. In animal studies, short-term expression of Yamanaka factors has reversed signs of aging in multiple tissues, including the retina, muscle, and brain, without generating tumors or losing cellular specialization.4 These findings have fueled optimism that controlled OKSM reprogramming could become a viable intervention to combat age-related degeneration and enhance longevity without the inherent risks of full reprogramming.5
As the field advances, the challenge remains to balance efficacy and safety. The ability to selectively rejuvenate cells while preserving their function represents a paradigm shift in aging research, with implications not only for extending life span but also for improving health span — the years of life spent in good health.
Understanding Cellular Aging and the Role of Epigenetics
Aging is a complex biological phenomenon driven by a combination of genetic, metabolic, and environmental factors that lead to a progressive decline in cellular and tissue function. At its core, aging is characterized by an accumulation of molecular damage, loss of regenerative capacity, and increased susceptibility to diseases such as cancer, neurodegeneration, and cardiovascular disorders. While the fundamental mechanisms of aging are multifaceted, several key processes contribute to the decline of cellular function over time.
One of the primary drivers of aging is the accumulation of DNA damage, which results from both intrinsic sources (e.g., oxidative stress and replication errors) and extrinsic factors (e.g., radiation and environmental toxins). DNA damage triggers cellular senescence, a state in which cells lose their ability to divide but remain metabolically active, often secreting pro-inflammatory molecules that contribute to tissue dysfunction.3 Senescent cells accumulate with age, creating a hostile pro-inflammatory environment that accelerates tissue degeneration.
Mitochondrial dysfunction is another hallmark of aging, as mitochondria are responsible for energy production and cellular metabolism. Over time, the efficiency of mitochondrial oxidative phosphorylation declines, leading to increased production of reactive oxygen species (ROS) that further damage cellular components, including DNA, proteins, and lipids. This creates a vicious cycle where impaired mitochondrial function exacerbates cellular aging.
In addition, aging is associated with loss of proteostasis, the cellular system responsible for maintaining protein quality and preventing the accumulation of misfolded proteins. Dysfunctional proteostasis mechanisms, including impaired autophagy and protein degradation pathways, lead to the accumulation of toxic protein aggregates, which are linked to neurodegenerative diseases like Alzheimer’s and Parkinson’s. Another key contributor to aging is telomere attrition, where the protective ends of chromosomes progressively shorten with each cell division. Once telomeres become critically short, cells enter senescence or apoptosis, further driving the aging process.6
While these molecular mechanisms drive cellular aging, recent research suggests that epigenetic modifications play a crucial role in determining biological age. Unlike genetic mutations, which are permanent, epigenetic modifications — such as DNA methylation, histone modifications, and chromatin remodeling — are reversible and serve as key regulators of gene expression. Studies have shown that aging is accompanied by systematic changes in DNA methylation patterns, a phenomenon quantified by epigenetic clocks, such as the Horvath clock, which can accurately predict biological age based on DNA methylation levels.6 These changes alter the expression of genes involved in metabolism, inflammation, and cellular repair, reinforcing the progressive decline associated with aging.
This epigenetic perspective has led to the hypothesis that cellular aging may not be an irreversible, unidirectional process but instead one that can be rewound through controlled reprogramming. OKSM reprogramming targets these epigenetic markers of aging, effectively restoring cells to a more youthful state. Unlike full reprogramming, which erases cellular identity and carries risks of tumor formation, partial reprogramming with transient expression of OKSM resets epigenetic age without inducing pluripotency.5
OKSM reprogramming works by remodeling chromatin, removing age-associated epigenetic modifications, and reactivating youthful gene expression programs.7 This process restores cellular function, improves mitochondrial efficiency, and enhances proteostasis, thereby counteracting key hallmarks of aging. Studies in mouse models have demonstrated that short-term induction of OKSM can rejuvenate aged tissues, improve organ function, and even extend life span without increasing cancer risk.5
Ultimately, the ability to reset epigenetic markers of aging through OKSM reprogramming represents a paradigm shift in aging research, with potential applications in age-related diseases, tissue regeneration, and longevity enhancement.
OKSM and Partial Cellular Reprogramming
The discovery of induced pluripotency using Yamanaka factors revealed the remarkable plasticity of cellular identity, demonstrating that differentiated adult cells could be reset to an embryonic-like state. However, fully reprogramming cells into iPSCs comes with significant risks, including tumorigenesis and loss of cellular identity. To mitigate these concerns, researchers have turned to partial cellular reprogramming, a method that selectively rejuvenates aging markers while maintaining cell function.
Mechanism of Action: How OKSM Resets Aging Markers
At the molecular level, OKSM reprogramming works by altering the epigenetic landscape of aged cells, primarily through chromatin remodeling. Chromatin, the tightly packed structure of DNA and histone proteins, dictates whether genes are accessible for transcription or silenced. Aging is associated with widespread heterochromatin loss, DNA hypermethylation in certain regions, and epigenetic drift, which disrupts normal gene expression patterns.8 The Yamanaka factors — Oct4, Sox2, Klf4, and c-Myc — play a direct role in resetting these modifications, thereby restoring a more youthful transcriptional profile.9
Oct4 and Sox2 act as pioneer transcription factors, opening previously inaccessible chromatin regions and reactivating genes associated with stemness and cellular repair. Klf4 reinforces chromatin accessibility, while c-Myc amplifies transcriptional activity, accelerating the epigenetic reset. Together, these factors erase age-related methylation marks, restore youthful gene expression, and improve mitochondrial function, counteracting major hallmarks of aging. However, if expressed continuously, this process drives cells toward full dedifferentiation, which is undesirable for regenerative applications.
To avoid complete loss of cellular identity, partial reprogramming strategies involve transient induction of OKSM, allowing cells to recover youthful epigenetic signatures without erasing differentiation markers. This controlled approach has been demonstrated in multiple studies to rejuvenate aged tissues, improve organ function, and extend life span without the risks associated with full reprogramming.5
OKSM vs. OSK: Balancing Reprogramming Efficiency and Safety
A major concern in OKSM reprogramming is the inclusion of c-Myc, which, while highly effective at enhancing reprogramming efficiency, is also strongly oncogenic. c-Myc functions as a master regulator of cell proliferation, increasing transcriptional output across the genome.2 While this property accelerates cellular reprogramming, it also heightens the risk of uncontrolled cell growth, making it unsuitable for clinical applications.
To reduce oncogenic risk, researchers have investigated the use of OSK-only reprogramming, excluding c-Myc. Studies have shown that OSK alone is sufficient to induce epigenetic rejuvenation while avoiding the pro-tumorigenic effects associated with c-Myc. However, OSK reprogramming tends to be less efficient and requires longer exposure to achieve the same degree of epigenetic resetting. Safe reprogramming protocols aim to balance these factors by using short pulses of OKSM expression or alternative delivery methods, such as transient RNA-based induction, to prevent excessive cellular proliferation.4
The key to successful and safe aging reversal lies in time-limited reprogramming protocols, where OKSM expression is turned off before cells reach pluripotency. Studies have demonstrated that intermittent OKSM activation can reverse aging markers in multiple tissues without causing dedifferentiation or tumorigenesis. This technique has been tested in vivo with remarkable success, leading to improvements in muscle regeneration, brain function, and metabolic health.5
Experimental Evidence of Aging Reversal Using OKSM
The first major evidence supporting OKSM-based rejuvenation came from in vivo mouse studies, where researchers demonstrated that short-term Yamanaka factor expression extended life span and reversed tissue aging without inducing tumors.4 In these studies, aged mice treated with intermittent OKSM expression regained youthful gene expression profiles, exhibited improved organ function, and had increased resistance to age-related diseases. Notably, this effect was systemic, affecting multiple tissues, including the skin, liver, kidneys, and muscles.
Subsequent studies in human cell cultures have further validated these findings. Experiments using aged fibroblasts, neurons, and endothelial cells have shown that transient OKSM expression restores mitochondrial function, enhances cellular metabolism, and resets epigenetic clocks.10 These effects were observed without loss of cellular identity, supporting the feasibility of controlled reprogramming as an anti-aging intervention.11
Further supporting this approach, a recent study demonstrated that OKSM-based reprogramming reduces DNA damage accumulation and improves cellular resilience to stress, two critical factors contributing to biological aging.12 These findings suggest that OKSM reprogramming could serve as a therapeutic strategy for extending health span, rather than merely prolonging lifespan.
Experimental Evidence and Clinical Potential
The potential of OKSM-mediated reprogramming to reverse aging has been demonstrated through a series of landmark experiments in animal models and human cells, providing strong evidence that partial cellular reprogramming can restore youthful function without inducing full pluripotency. These findings pave the way for clinical applications in treating age-related diseases, improving tissue repair, and extending health span.
Animal Studies: Proof of Concept
The first major demonstration of OKSM’s rejuvenative effects in vivo came from a study conducted by Ocampo et al. (2017), which showed that transient expression of Yamanaka factors could reverse aging markers and restore tissue function in aged mice.4 In this study, researchers induced short-term OKSM expression in naturally aged and progeroid (premature aging) mice, observing widespread improvements in cellular function and tissue repair. Key findings included:
Improved muscle regeneration: Aged mice exhibited enhanced muscle repair after injury, demonstrating increased stem cell activity and improved mitochondrial function.
Brain rejuvenation: OKSM reprogramming led to reduced neuroinflammation and improved cognitive performance in older mice.
Skin and tissue repair: Aged mice undergoing partial reprogramming regained youthful gene expression patterns, leading to thicker, more resilient skin and improved wound healing.
A particularly striking result was the restoration of vision in aged mice. In a subsequent study, researchers demonstrated that OSK (excluding c-Myc) could restore retinal function in mice with age-related vision loss, specifically targeting damaged retinal ganglion cells.4 This marked the first successful demonstration of in vivo epigenetic rejuvenation in a complex tissue, suggesting that controlled OKSM reprogramming could be used to reverse degenerative diseases without genetic modification.
Building on these findings, recent work has shown that lifespan extension is possible through partial reprogramming. Macip (2024) reported that intermittent OKSM activation in mice led to a significant increase in life span, correlating with improved metabolic efficiency and reduced markers of cellular stress.5 Notably, tumor formation was not observed, confirming that careful control of reprogramming factors can mitigate oncogenic risks.
In Vitro Applications: Resetting Age in Human Cells
The successes observed in animal models have been further validated in human cell culture studies, demonstrating that transient OKSM expression can reset biological age markers and restore cellular function.
Xiao (2022)10 examined the effects of partial reprogramming on human fibroblasts, revealing that short-term OKSM exposure led to:
Rejuvenation of mitochondrial function, reversing age-related declines in ATP production and oxidative stress.
Restoration of youthful gene expression, aligning transcriptomic profiles with those of younger cells.
Increased cellular resilience, as aged fibroblasts showed enhanced stress resistance and improved DNA repair mechanisms.
Beyond fibroblasts, OKSM reprogramming has shown promise in neuronal and immune cells. Yang (2023) reported that transient OKSM expression in aged human neurons led to increased synaptic plasticity, suggesting potential applications for treating neurodegenerative diseases such as Alzheimer’s and Parkinson’s.13 Similarly, studies on aged immune cells demonstrated that partial reprogramming can restore immune function, potentially enhancing vaccine response and reducing age-related immunodeficiency.
Collectively, these studies provide strong evidence that OKSM-based interventions can restore function in aged human cells, reinforcing the feasibility of clinical applications.
Potential Clinical Applications
As research progresses, OKSM reprogramming holds significant promise for therapeutic applications, particularly in treating diseases where aging is a primary risk factor. Simpson (2021)7 and Abd (2023)11 have explored several potential areas for clinical translation:
Neurodegenerative Diseases
Aging is the biggest risk factor for neurodegenerative disorders, including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS).
Partial reprogramming could restore neuronal function by reversing epigenetic aging in neurons, improving synaptic plasticity, and reducing neuroinflammation.
Experimental models suggest that OKSM may help restore memory function and motor control, making it a promising strategy for neurodegenerative disease therapy.
Cardiovascular Aging
Aging contributes to heart failure, arterial stiffening, and fibrosis, reducing the heart’s ability to pump blood efficiently.
OKSM-based reprogramming has been shown to reduce cardiac fibrosis and improve contractility in aging heart cells.
In vivo studies indicate that reprogramming may help regenerate damaged myocardial tissue, offering a potential treatment for ischemic heart disease and heart failure.
Metabolic Disorders and Diabetes
Age-related metabolic decline is linked to insulin resistance, mitochondrial dysfunction, and systemic inflammation, all of which contribute to type 2 diabetes and obesity-related diseases.
Partial reprogramming has been shown to improve insulin sensitivity in aged cells, potentially reversing aspects of age-related diabetes.
OKSM-mediated rejuvenation of pancreatic beta cells could restore glucose homeostasis, reducing dependency on insulin therapy.
Challenges and Risks of OKSM Reprogramming
While OKSM reprogramming holds immense promise for reversing aging and treating age-related diseases, its clinical translation remains complex. Several key challenges must be addressed before these approaches can be safely and effectively applied in humans. These challenges include oncogenic risks, technical limitations in delivery, and ethical considerations regarding lifespan extension and regulatory oversight.
Oncogenic Potential and Tumorigenesis
One of the most significant concerns associated with OKSM reprogramming is the potential for tumorigenesis, particularly if reprogramming proceeds beyond a safe threshold. The inclusion of c-Myc in the Yamanaka factor set is particularly problematic, as it is a well-documented oncogene involved in uncontrolled cell proliferation.2 If cells are pushed too far along the dedifferentiation pathway, they may enter a proliferative, undifferentiated state that can lead to the formation of teratomas or cancerous growths.
Studies have demonstrated that indiscriminate or prolonged expression of OKSM can increase genomic instability, further elevating the risk of malignancy.11 To mitigate these risks, researchers have developed several strategies to control reprogramming:
Time-restricted OKSM induction: Instead of continuous expression, OKSM factors are activated in short pulses, allowing epigenetic rejuvenation without full dedifferentiation.
OSK-only reprogramming: By excluding c-Myc, the oncogenic potential of the reprogramming cocktail is reduced, while still achieving partial rejuvenation.
Small molecule-based reprogramming: Recent efforts focus on using chemical modulators instead of direct gene expression, reducing the risk of genetic instability and uncontrolled proliferation.
The success of these approaches in animal models suggests that careful modulation of reprogramming duration and factor selection can reduce oncogenic risks, but further long-term studies are needed before human applications can be considered safe.
Technical Barriers to Clinical Translation
Beyond safety concerns, significant technical hurdles remain in delivering OKSM factors efficiently and precisely to aging cells and tissues.
Delivery Challenges: Viral vs. Non-Viral Approaches
Currently, most OKSM reprogramming studies use viral vectors (such as lentiviruses or adeno-associated viruses) to deliver transcription factors into cells. While effective, viral-based delivery presents several risks:
Insertional mutagenesis: Random viral integration into the genome could disrupt essential genes, potentially leading to unintended genetic alterations or tumorigenesis (Longenia).
Immune response concerns: The human immune system can recognize viral components as foreign, leading to inflammatory responses that could reduce the effectiveness of the therapy.
To address these limitations, researchers are exploring non-viral delivery methods, including:
mRNA-based delivery: Transient expression of OKSM via mRNA avoids permanent genomic alterations, reducing long-term risks.10
Nanoparticle-based delivery: Synthetic lipid nanoparticles (LNPs) have shown promise in delivering reprogramming factors without triggering immune reactions.
CRISPR activation (CRISPRa): Instead of delivering transcription factor genes, researchers can use CRISPR-based gene activation to induce endogenous OKSM expression, minimizing the risks associated with external gene delivery.
While these approaches offer safer and more precise alternatives, challenges remain in achieving tissue-specific targeting, optimizing dosing, and ensuring reproducibility across different cell types.
Precision Control Over Factor Expression
An ideal reprogramming therapy would allow for precise control over OKSM factor expression, ensuring that cells receive just enough stimulation to reset epigenetic markers without crossing into full dedifferentiation. However, existing delivery methods lack fine control over:
Dosage and timing: Overexpression risks cellular instability, while underexpression limits rejuvenation effects.
Cell-type specificity: Different tissues may respond differently to OKSM, necessitating customized protocols.
Long-term stability: Ensuring that reprogramming effects persist without requiring repeated treatments remains an open question.
Emerging strategies, such as inducible gene circuits and self-regulating feedback loops, may help fine-tune OKSM expression to maximize safety and efficacy, but these technologies are still in their early stages of development.
Ethical and Regulatory Considerations
Beyond scientific and technical challenges, OKSM reprogramming raises profound ethical and regulatory questions, particularly concerning human life span extension and societal implications.
Concerns About Human Lifespan Extension
The idea of reversing aging has sparked ethical debates regarding:
Equitable access: If OKSM-based longevity therapies become available, who will have access? Will it be a treatment only for the wealthy, exacerbating health inequities?
Social consequences: Prolonging life span could have unintended effects on population growth, resource allocation, and economic structures.
Identity and quality of life: If biological aging can be reversed, what defines an individual’s natural life course? How will an extended life span affect mental health, generational roles, and social stability?
These concerns suggest that any attempt to translate reprogramming-based rejuvenation into clinical use must be guided by ethical frameworks that consider both individual and societal consequences.12
Regulatory Landscape for Clinical Approval
The regulatory path for OKSM-based therapies remains uncertain, as no partial reprogramming treatments have yet been approved for clinical use. Regulatory agencies, such as the FDA and EMA, will likely scrutinize several aspects of OKSM interventions:
Long-term safety: Proving that OKSM-induced rejuvenation does not lead to genomic instability or long-term health risks will require extensive preclinical and human trials.6
Efficacy validation: Demonstrating clear functional improvements in human trials will be necessary to gain regulatory approval.
Therapeutic vs. enhancement classification: Will OKSM be classified as a therapeutic for age-related diseases or as a general longevity enhancement? This distinction will significantly impact regulatory requirements and public acceptance.
Given these challenges, researchers and policymakers must work collaboratively to define ethical and regulatory guidelines that balance scientific progress with public safety.
While OKSM-mediated reprogramming offers unprecedented potential for reversing aging and treating degenerative diseases, several critical hurdles must be overcome before it can be translated into clinical applications. Oncogenic risks, technical barriers in delivery, and ethical considerations surrounding life span extension all require careful navigation.
Future Directions and Conclusion
The field of OKSM-mediated reprogramming is at a pivotal moment, where scientific advancements are rapidly expanding its potential applications while significant hurdles remain in its translation to human therapies. As research continues, novel approaches aim to enhance safety, improve efficiency, and refine clinical strategies to harness partial reprogramming as a viable intervention for aging and age-related diseases.
Next-Generation Reprogramming Strategies
One of the most promising advancements in reprogramming research is the development of chemical reprogramming alternatives, which eliminate the need for direct genetic modification. Instead of using viral vectors to deliver OKSM factors, researchers have identified small-molecule cocktails capable of inducing similar epigenetic rejuvenation effects. Yang (2023) demonstrated that a combination of chemical compounds could mimic the effects of Yamanaka factors, resetting epigenetic markers associated with aging while reducing the risk of tumorigenesis.13 This approach offers several advantages, including greater precision, reduced immune response, and easier clinical implementation compared to gene-based reprogramming.
Additionally, CRISPR-based strategies are being explored to enhance the safety and specificity of cellular reprogramming. CRISPRa allows for the controlled upregulation of endogenous OKSM genes, rather than introducing external transcription factors. This method provides a more targeted and temporary induction of rejuvenation pathways, further minimizing the risk of genetic instability and uncontrolled proliferation. These advances suggest that future reprogramming therapies may combine gene editing, chemical modulation, and advanced delivery mechanisms to optimize both efficacy and safety.
The Road to Clinical Application
Despite the remarkable progress in preclinical studies, OKSM-based reprogramming is still far from widespread clinical use. Several key milestones must be reached before it can become an approved medical intervention:
Large-scale clinical trials: To establish safety and efficacy, extensive human trials will be required, testing reprogramming strategies in various tissues and patient populations.
Regulatory acceptance: Agencies such as the FDA and EMA will need to establish new frameworks for evaluating partial reprogramming therapies, ensuring that they meet rigorous safety standards.
Scalability and accessibility: The development of cost-effective delivery systems, whether through mRNA, nanoparticles, or chemical formulations, will be essential for widespread adoption.
While some researchers predict that early-stage human trials could begin within the next 5-10 years, full regulatory approval for anti-aging therapies may take decades to achieve.12 However, targeted applications — such as treating neurodegenerative diseases or cardiovascular aging — could reach clinical use sooner if sufficient safety data is obtained.11
Final Thoughts: Can We Truly Reverse Aging?
The ability to reverse aging at the cellular level challenges traditional views on biological decline and life span limitations. However, the goal of reprogramming is not merely to extend life but to enhance health span —ensuring that individuals remain healthy, functional, and disease-free as they age.
The future of OKSM-based interventions will depend on achieving a delicate balance between rejuvenation and biological stability. If precisely controlled, these therapies could revolutionize medicine, providing new treatments for age-related diseases and extending human vitality well beyond current expectations. While many obstacles remain, the promise of OKSM reprogramming is undeniable, and its continued exploration represents one of the most exciting frontiers in regenerative medicine and longevity science.
Our parent company, That’s Nice, is committed to supporting the companies and innovators driving the next wave of pharma and biotech innovation. To celebrate That’s Nice’s 30th anniversary, Pharma’s Almanac is diving into 30 groundbreaking advancements, trends, and breakthroughs that have shaped the life sciences, highlighting the industry-defining milestones our agency has had the pleasure of growing alongside. Here’s to 30 years of innovation and the future ahead!
References
1. Takahashi, Kazutoshi and Shinya Yamanaka. “Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors."Cell 126: 663–676 (2006).
2. Gong, Lanqi, et al. “Cancer cell reprogramming: a promising therapy converting malignancy to benignity.” Cancer Communications. 39: 48 (2019).
3. Chronis, Constantinos, et al. “Cooperative binding of transcription factors orchestrates reprogramming.” Cell. 168: 442–459.e20 (2018).
4. Ocampo, Alejandro, et al. “In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming.” Cell. 167: 1719–1733.e12 (2017).
5. Macip, Carolina Cano, et al. “Gene Therapy-Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice.” Cellular Reprogramming. 15 Feb. 2024.
6. Horvath, Steve et al. “Cognitive rejuvenation in old rats by hippocampal OSKM gene therapy." Geroscience. 47: 809-823 (2025).
7. Simpson, Daniel, Nelly N Olova, and Tamir Chandra. “Cellular reprogramming and epigenetic rejuvenation.” Clinical Epigenetics. 13: 170 (2021).
8. Soufi, Abdenour, Greg Donahue, and Kenneth S Zaret. “Facilitators and Impediments of the Pluripotency Reprogramming Factors' Initial Engagement with the Genome.” Cell. 141: 994-1004 (2012).
9. Soufi, Abdenour, Greg Donahue, and Kenneth S Zaret. “Facilitators and Impediments of the Pluripotency Reprogramming Factors’ Initial Engagement with the Genome.” Cell. 141: 994–10042013.
10. Xiao, Xue, et al. “Concise review: Cancer cell reprogramming and therapeutic implications.” Translational Oncology. 24:101503 (2022).
11. Abd, Genevieve M, et al. “Hypoxia-induced cancer cell reprogramming: a review on how cancer stem cells arise.” Front. Oncol. 7 Aug. 2023.
12. Paine, Patrick T, Ada Nguyen, and Alejandro Ocampo. “Partial cellular reprogramming: A deep dive into an emerging rejuvenation technology.” Cell. 23: e14039 (2023).
13. Yang, Jae-Hyun, et al. “Chemically induced reprogramming to reverse cellular aging.” Aging. 15: 5966–5989 (2023).