EB: If you can administer zero age your own pluripotent cells which do not form teratomas and can technically replace your all old stem cells - can you accomplish radical rejuvenation then? or something else needed to be addressed? While replacing all old stem cells with zero-age pluripotent cells that do not form teratomas could potentially lead to significant rejuvenation, it is unlikely to accomplish radical rejuvenation on its own. Several other factors would need to be addressed: Cellular Rejuvenation Replacing old stem cells with young pluripotent cells could indeed provide substantial benefits: 1. Renewed regenerative capacity 2. Improved tissue repair and maintenance 3. Restoration of youthful gene expression patterns However, this approach alone may not be sufficient for radical rejuvenation due to other age-related changes that occur beyond stem cell aging. Additional Factors to Address Epigenetic Alterations Epigenetic changes accumulate with age across all cells, not just stem cells. These include: • DNA methylation patterns • Histone modifications • Chromatin remodeling Resetting these epigenetic marks may require more comprehensive reprogramming approaches 9 . Senescent Cells The accumulation of senescent cells contributes significantly to aging. Eliminating these cells, in addition to stem cell replacement, would be crucial for comprehensive rejuvenation 8 . Extracellular Matrix (ECM) Changes Age-related changes in the ECM, including crosslinking and degradation, affect tissue function and stem cell behavior. Addressing ECM alterations would be necessary for full rejuvenation 5 . Systemic Factors Circulating factors in the blood and other bodily fluids influence aging across tissues. Modulating these systemic factors may be required for complete rejuvenation 1 . Mitochondrial Dysfunction Aging is associated with mitochondrial damage and dysfunction. Rejuvenating or replacing mitochondria may be necessary for radical life extension 6 . Protein Homeostasis Accumulation of misfolded proteins and decline in protein quality control systems contribute to aging. Restoring proteostasis would be crucial for comprehensive rejuvenation 9 . Potential Approaches To achieve radical rejuvenation, a multi-faceted approach combining several strategies may be necessary: 1. Stem cell replacement with young pluripotent cells 2. Partial cellular reprogramming to reset epigenetic age 9 3. Senolytic therapies to eliminate senescent cells 4. ECM remodeling and crosslink breaking 5. Systemic rejuvenation factors (e.g., young blood factors) 6. Mitochondrial rejuvenation or replacement 7. Enhanced proteostasis mechanisms In conclusion, while replacing all stem cells with zero-age pluripotent cells could provide significant benefits, radical rejuvenation would likely require addressing multiple hallmarks of aging simultaneously. The complexity of the aging process necessitates a comprehensive approach targeting various cellular and tissue-level changes to achieve transformative life extension. EB: Jus a sec, but if you can replace old stem cells than they will take care of specialized cells, that what you gave to me You raise an important point about the relationship between stem cells and specialized cells in the context of rejuvenation. While replacing old stem cells with young ones could indeed lead to significant improvements, it's not a complete solution for addressing all age-related epigenetic changes. Here's why: 1. Persistence of epigenetic alterations: Even if you replace old stem cells with young ones, the existing specialized cells in the body would still retain their age-associated epigenetic marks 1 . These cells would continue to exhibit signs of aging until they are naturally replaced by the progeny of the new stem cells. 2. Gradual replacement: The turnover of specialized cells varies greatly between tissues. Some cells, like those in the gut lining, are replaced frequently, while others, like neurons, can persist for a lifetime 5 . This means that the rejuvenation effect would be gradual and tissue-dependent. 3. Environmental factors: The tissue microenvironment, which includes factors like the extracellular matrix and circulating molecules, can influence the epigenetic state of cells 6 . Even with young stem cells, this aged environment could potentially induce some age-related epigenetic changes in their progeny. 4. Cellular memory: Some epigenetic marks are highly stable and can persist through cell divisions 7 . This "epigenetic memory" might not be completely erased simply by introducing young stem cells. 5. Non-stem cell aging: Some age-related epigenetic changes occur in non-dividing cells that are not regularly replaced by stem cells 8 . These changes would not be addressed by stem cell replacement alone. To achieve more comprehensive rejuvenation, additional strategies might be necessary: 1. Direct epigenetic reprogramming: Techniques like partial reprogramming or targeted epigenetic editing could help reset age-related marks in existing specialized cells 2 3 . 2. Systemic factors: Modulating the overall tissue environment, perhaps through interventions that affect circulating factors, could support more widespread epigenetic rejuvenation 4 . 3. Combination approaches: Integrating stem cell replacement with other rejuvenation strategies might provide more thorough and lasting effects. In conclusion, while replacing old stem cells with young ones is a powerful approach, it's likely that additional interventions targeting epigenetic alterations directly would be needed for more complete rejuvenation across all cell types. EB: But eventually all specialized cells will be replaced what is the problem then with epigenetic memory? While it's true that specialized cells are eventually replaced, epigenetic memory in stem cells can still pose challenges for complete rejuvenation: 1. Gradual replacement: The turnover rate of specialized cells varies greatly between tissues. Some cells, like those in the gut lining, are replaced frequently, while others, like neurons, can persist for a lifetime 4 . This means that the rejuvenation effect would be gradual and tissue-dependent. 2. Persistent epigenetic marks: Some epigenetic marks are highly stable and can persist through cell divisions. This "epigenetic memory" might not be completely erased simply by introducing young stem cells 4 . 3. Environmental factors: The tissue microenvironment, including factors like the extracellular matrix and circulating molecules, can influence the epigenetic state of cells. Even with young stem cells, this aged environment could potentially induce some age-related epigenetic changes in their progeny 4 . 4. Stem cell aging: Epigenetic alterations in stem cells themselves can affect their function and differentiation potential. These changes can be propagated to daughter cells and influence tissue homeostasis over time 3 . 5. Non-dividing cells: Some age-related epigenetic changes occur in non-dividing cells that are not regularly replaced by stem cells. These changes would not be addressed by stem cell replacement alone 4 . To achieve more comprehensive rejuvenation, additional strategies might be necessary: 1. Direct epigenetic reprogramming of existing cells 2. Modulation of the overall tissue environment 3. Combination approaches integrating stem cell replacement with other rejuvenation strategies 4 In conclusion, while replacing old stem cells with young ones is a powerful approach, addressing epigenetic memory and other age-related changes in the cellular environment is likely necessary for more complete rejuvenation across all cell types. EB: Wouldn't even slow cell turnover eventually replace ECM? it is not a stone or metal after all While cell turnover does contribute to ECM renewal, it's not sufficient to fully address age-related ECM changes for several reasons: 1. Accumulation of crosslinks: With age, ECM proteins like collagen and elastin develop crosslinks that are resistant to normal turnover processes 7 . These crosslinks, often caused by glycation or oxidation, make the ECM stiffer and less amenable to remodeling. 2. Imbalance in production and degradation: Aging leads to a decline in ECM biosynthesis and an increase in degradation 7 . This imbalance results in a net loss of ECM components over time, which cell turnover alone may not fully compensate for. 3. Changes in ECM composition: The relative proportions of different ECM components change with age 6 . For example, there's often an increase in certain types of collagen and a decrease in others, which affects tissue properties. 4. Cellular senescence: As cells age, their ability to produce and maintain a healthy ECM diminishes 5 . This means that even with continued cell turnover, the quality of the newly produced ECM may be compromised. 5. Persistent damage: Some ECM components, particularly in tissues with low turnover rates, can accumulate damage faster than they can be replaced 7 . This is especially true for long-lived proteins like some types of collagen. 6. Environmental factors: The tissue microenvironment, including factors like chronic inflammation and oxidative stress, can continuously impact the ECM, outpacing the ability of cell turnover to maintain its integrity 1 . To achieve full rejuvenation, targeted interventions may be necessary to address these specific ECM alterations. This could include strategies to break crosslinks, enhance ECM production, modulate the balance of ECM components, and improve the overall quality of newly synthesized ECM 4 . Additionally, addressing the underlying causes of ECM deterioration, such as cellular senescence and chronic inflammation, would be crucial for comprehensive rejuvenation. EB: What are the latest advances to fight the rigidity of ECM, list 10 latest and the most efficient ones: Based on the latest research, here are 10 of the most promising and efficient approaches to combat extracellular matrix (ECM) rigidity in cancer: 1. Targeting Lysyl Oxidase (LOX): Inhibiting LOX enzymes, which are responsible for collagen crosslinking, can reduce ECM stiffness. The pan-LOX inhibitor PXS-5505 has shown promise in preclinical studies for decreasing collagen stiffening and improving drug delivery 8 . 2. Collagen Crosslink Disruption: Developing agents that can break existing collagen crosslinks, particularly focusing on glucosepane, a major crosslink in aging and diabetes 1 . 3. CAF Modulation: Targeted activation or inhibition of cancer-associated fibroblasts (CAFs) to alleviate ECM remodeling and reduce tumor stiffness 3 . 4. Engineered Biomaterials: Using synthetic 3D hydrogels with tunable physicochemical properties to study and potentially modulate ECM stiffness in cancer 1 . 5. Metabolic Glycoengineering: Novel approaches to chemically functionalize natural matrices, such as incorporating azide moieties, to facilitate better control over matrix properties 1 . 6. TGFβ Signaling Inhibition: Targeting TGFβ signaling to normalize the tumor microenvironment by affecting CAFs 8 . 7. ROCK Inhibition: Modulating the Rho kinase (ROCK) pathway, which acts as a mechanosensor for matrix stiffness, to reduce ECM component synthesis 2 . 8. Targeting Extracellular Vesicles: Focusing on the role of extracellular vesicles in cellular communication and aging processes to potentially reduce ECM stiffness 1 . 9. Hyaluronic Acid-based Interventions: Developing HA-based hydrogels to mimic and modulate the peritumoral region's softer ECM, influencing tumor cell behavior 8 . 10. Integrin-targeted Therapies: Developing treatments that target integrin mechanosignaling to disrupt the effects of stiff ECM on tumor cells 8 . These approaches represent the cutting edge in combating ECM rigidity, offering potential for improving drug delivery, enhancing immune cell infiltration, and ultimately increasing the efficacy of cancer treatments. EB: If you introduce a lot of pluripotent with age 0 stem cells, can eventually like in 10 years they will replace old rigid matrix? While introducing a large number of pluripotent stem cells with age 0 could potentially contribute to tissue regeneration and extracellular matrix (ECM) remodeling over time, it is unlikely that they would completely replace the old rigid matrix within 10 years. Here's why: Challenges in ECM Replacement 1. ECM Turnover Rate: The turnover rate of ECM components varies significantly between tissues and can be quite slow, especially in tissues with low cellular activity. 2. Persistent Crosslinks: Age-related crosslinks in the ECM, particularly those formed through glycation (like glucosepane), are highly resistant to degradation and turnover 1 . 3. Environmental Factors: The aged tissue microenvironment, including factors like chronic inflammation and oxidative stress, can continue to impact newly synthesized ECM 6 . Stem Cell Behavior in Aged Environments 1. Differentiation Challenges: The aged ECM can influence stem cell behavior and differentiation. Pluripotent stem cells may not efficiently differentiate into the required cell types in an aged environment 7 . 2. Cell Survival: Poor post-transplantation viability of stem cells is a significant limitation in stem cell therapy 8 . 3. ECM Interactions: The existing aged ECM may not provide optimal cues for stem cell function and tissue regeneration 5 . Potential for Partial Rejuvenation Despite these challenges, introducing young pluripotent stem cells could lead to some degree of tissue rejuvenation: 1. Local ECM Remodeling: Stem cells and their progeny could produce new ECM components, potentially improving the local microenvironment 2 . 2. Paracrine Effects: Stem cells may secrete factors that promote tissue repair and reduce inflammation, indirectly improving ECM quality 10 . 3. Cell Replacement: Over time, stem cell-derived cells could replace some aged cells, contributing to tissue function improvement 9 . Conclusion While introducing young pluripotent stem cells has the potential to improve tissue health and partially remodel the ECM, complete replacement of the old rigid matrix within 10 years is unlikely due to the persistent nature of some age-related ECM modifications and the complex interplay between cells and their microenvironment. A more realistic expectation would be a gradual improvement in tissue function and partial ECM rejuvenation, rather than complete replacement of the aged matrix.