Longevity Questions

Vitalii Bardichev, [06.05.2025 22:27]
Reprogramming Factor Questions:

Unique mechanistic roles of Oct4 and dose sensitivity:

147. Pioneer factor specificity in old chromatin: how does Oct4 pioneer activity specifically interact with and open up age-compacted chromatin regions, and are there age-specific cofactors or chromatin states that uniquely modulate Oct4 binding and action relative to its role in ES cells?

148. Non-redundant epigenetic reset: what specific age-associated epigenetic marks (e.g., DNA methylation patterns, histone modifications) are uniquely and directly targeted and reverted by Oct4 that cannot be achieved (or is not as effective) by Sox2, Klf4, or Nanog alone or in other combinations?

149. Oct4 dosage for rejuvenation versus pluripotency: Given the extreme dose sensitivity of Oct4 in determining pluripotency, what are the precise in vivo molecular thresholds and downstream signaling cascades that distinguish safe Oct4-induced rejuvenation from initiation of full pluripotency or teratoma formation in aged somatic cells?

150. Direct versus indirect target genes for rejuvenation: Which genes critical for reversing cellular senescence are direct transcriptional targets of Oct4 (bound by Oct4 at their regulatory elements), versus those that are indirectly affected via Oct4 modulation of other signaling pathways or transcription factors in aged cells?

151. Role in mitochondrial rejuvenation: Does Oct4 directly affect mitochondrial genome expression, mitochondrial biogenesis, or mitophagy pathways in aged cells, and if so, are these effects distinct from its nuclear epigenetic roles?

152. Oct4 isoform specificity (Oct4A vs. Oct4B): Does the predominant Oct4A isoform (nuclear, pluripotency-associated) have different rejuvenation benefits or risks in aged cells compared to Oct4B isoforms (cytoplasmic, stress response-associated), and can specific isoforms be targeted?

Safety and tumorigenesis (Oct4-related issues):

153. Earliest oncogenic events induced by Oct4: What are the earliest molecular events (e.g., derepression of a specific gene, reactivation of developmental pathways) specifically induced by inappropriate Oct4 re-expression in aged somatic cells that initiate the pathway to tumorigenesis, especially teratomas?

154. Interaction with age-accumulated somatic mutations: How do pre-existing somatic mutations in critical oncogenes or tumor suppressors (common in aged tissues) specifically alter the cellular response to transient Oct4 expression, potentially lowering the threshold for transformation?

155. The “point of no return” in Oct4-induced dedifferentiation: During transient Oct4 expression, what is the molecular “point of no return” beyond which the aged somatic cell loses its original identity and adopts a pluripotent or cancer fate, and can this be precisely controlled?

156. Oct4-specific off-target effects: In addition to general epigenetic changes, are there specific off-target genomic changes (e.g., in Oct4 pseudogenes, repetitive elements) or proteotoxic stress responses uniquely induced by ectopic Oct4 expression in aged cells?

Oct4 in the context of cells and organisms:

157. Cell type-specific susceptibility of Oct4 to rejuvenation: are certain types of aged cells intrinsically more or less susceptible to Oct4-mediated rejuvenation due to their basal epigenetic state, endogenous Oct4-interacting partners, or lineage-specific chromatin architecture?

Vitalii Bardichev, [06.05.2025 22:27]
158. Impact of endogenous Oct4 pseudogenes: how does the expression or potential function of endogenous Oct4 pseudogenes (which can be transcribed and sometimes translated) in aged tissues influence or contribute to the rejuvenating effects of exogenously administered Oct4?

159. Downstream effectors mediating the systemic benefits of Oct4: If transient expression of Oct4 in a single tissue shows systemic benefits (as some studies suggest), what Oct4-dependent secreted factors or intercellular communication pathways are responsible for these distal effects?

160. Defining the role of Oct4 in “rejuvenation memory”: If cells are transiently exposed to Oct4, do they retain an epigenetic “memory” that makes them more resilient to future aging or more responsive to subsequent, milder rejuvenation signals? What is the Oct4-dependent basis for this?

Translational and therapeutic features of Oct4:

161. Optimizing the dynamics of short-term Oct4 delivery: What are the optimal kinetics (peak level, duration, frequency of delivery pulses) of Oct4 expression in vivo for maximal rejuvenation in a variety of aged tissues, while specifically avoiding teratoma formation or loss of specialized cellular function?

162. Oct4-specific biomarkers of safe rejuvenation: what reliable biomarkers (other than general pluripotency markers such as Nanog or SSEA-1, if targeting partial reprogramming) can specifically indicate that Oct4 is inducing beneficial rejuvenation without initiating dedifferentiation or oncogenic pathways?

163. Synergistic partners for Oct4-mediated rejuvenation (beyond OSKM): are there non-OSKM factors or small molecules that can specifically enhance the rejuvenating effects of Oct4?

164. Mechanism of Oct4 action on the aging immune system: does Oct4 expression directly modulate immune cell function (if targeted) or indirectly alter the immunogenicity of rejuvenated somatic cells, and how does this impact long-term safety and efficacy?

165. Long-term stability of Oct4-induced rejuvenation: after cessation of transient Oct4 expression, how stable are the rejuvenated epigenetic and functional states in aged cells? What Oct4-initiated mechanisms contribute to the maintenance (or eventual loss) of these benefits?

166. Small molecules to mimic the rejuvenating downstream effects of Oct4: can specific downstream pathways required for the rejuvenating (but not pluripotent) effects of Oct4 be identified and selectively activated by small molecules, thereby bypassing direct Oct4 gene therapy?

Vitalii Bardichev, [06.05.2025 22:28]
Focus on the nervous and sensory system (Sox2 strength):

167. Optimizing neural stem cell rejuvenation: can targeted, transient expression of Sox2 (alone or in specific combinations) effectively rejuvenate aged neural stem/progenitor cells in situ to improve cognitive function or repair age-related neural damage without inducing tumors?

168. Restoring sensory function: Given the role of Sox2 in inner ear and eye development, can its controlled re-expression in aged sensory organs (e.g., cochlear hair cells, retinal cells) restore lost sensory acuity, and what is the molecular basis?

169. Combating neuroinflammation: does Sox2 expression influence the aged brain microenvironment, specifically by modulating microglial and astrocyte phenotypes to reduce chronic neuroinflammation and promote a pro-regenerative state?

170. Differential roles in neurodegenerative diseases: how does Sox2 (or its dysregulation) promote or protect against certain age-related neurodegenerative diseases (e.g., Alzheimer's, Parkinson's), and could Sox2 modulation be a therapeutic option?

171. Sox2 isoforms and longevity: do different Sox2 isoforms or post-translationally modified versions play distinct roles in cellular aging and rejuvenation, particularly in the nervous system?