Longevity Questions

Vitalii Bardichev, [06.05.2025 22:32]
Translational and Broader Biological Questions:

222. Synergy with Other Reprogramming Factors or Longevity Pathways: How does Lin28 interact with other reprogramming factors (e.g., OSK) or known longevity pathways (e.g., mTOR, sirtuins) in the pursuit of rejuvenation? Is there synergy or antagonism?

223. Small Molecules Mimicking Lin28 Function: Can small molecules be designed that specifically mimic the beneficial RNA binding properties of Lin28 (e.g., let-7 suppression) or activate its downstream rejuvenation pathways without direct gene delivery?

224. Lin28 and “Inflammaging”: How does Lin28 expression influence chronic, low-grade inflammation associated with aging (“inflammaging”)? Does it suppress pro-inflammatory pathways or enhance anti-inflammatory responses?

225. Impact on the epigenome (indirectly): Although not a direct epigenetic modifier like Oct4, how do Lin28-mediated changes in RNA processing and target gene expression (e.g., epigenetic regulators) indirectly alter the epigenetic landscape of aged cells toward a more youthful state?

226. Biomarkers of Lin28-mediated rejuvenation: What are reliable and specific biomarkers (e.g., changes in let-7 target levels, metabolic shifts) that can monitor the efficacy and safety of Lin28-based interventions in preclinical models and eventually in humans?

Vitalii Bardichev, [06.05.2025 22:35]
Maintenance of Pluripotency and Ground State:

227. Transient Induction of the “Ground State”: Can transient expression of Nanog (possibly with specific partners such as Esrrb) induce a transient, rejuvenation-permissive “ground state-like” epigenetic configuration in aged somatic cells without locking them into full pluripotency?

228. Role in Partial Reprogramming Specificity: When Nanog is included in partial reprogramming cocktails, what unique molecular contribution does it make to rejuvenation that is distinct from or synergistic with Oct4, Sox2, and Klf4?

229. Nanog and heterogeneity of rejuvenation: Given the fluctuating expression of Nanog in pluripotent cells, does transient expression of Nanog in aged cells result in a heterogeneous response, and can we identify/select an optimally rejuvenated subpopulation?

230. Stabilization of rejuvenated cell identity: Could Nanog, known to stabilize pluripotency, play a role in stabilizing rejuvenated somatic cell identity after partial reprogramming, preventing re-senescence or loss of function?

Adult stem cells and tissue-specific roles:

231. Rejuvenation of specific adult stem cell niches: Does Nanog play a preferential role in rejuvenating specific adult stem cell populations (e.g., in the brain, muscle, or hematopoietic system) that are particularly vulnerable to aging, and how does it achieve this?

232. Nanog in germline longevity: Given its important role in primordial germ cells, does Nanog or its downstream pathways hold keys to exceptional germline longevity and epigenetic resilience that could be applied to somatic cells?

233. Context-specific interactions in aged tissues: How do Nanog protein-protein interactions and downstream target genes differ in aged somatic cells compared to embryonic stem cells, and how does this determine its rejuvenation versus pluripotency-inducing potential?

Mechanisms of action and cellular processes:

234. Unique epigenetic signatures: Which specific age-related epigenetic marks are uniquely responsive to Nanog expression, and how does this differ from broader epigenetic remodeling driven by factors such as Oct4?

235. Impact on Chromatin Accessibility and Higher-Order Structure: How does Nanog specifically impact higher-order chromatin structure and regulatory element accessibility in aged cells, promoting a more youthful transcriptional landscape?

236. Nanog and Cellular Stress Resistance: Can Nanog expression enhance resistance to cellular stressors associated with aging (e.g., oxidative stress, proteotoxicity, DNA damage) beyond what other reprogramming factors achieve?

237. Modulation of Cell Cycle Re-entry: How does Nanog impact cell cycle re-entry or exit in aged, often quiescent, or senescent cells? Can it promote beneficial proliferation for repair without uncontrolled division?

Safety, Oncogenesis, and Control:

238. Dissecting the Role of Nanog in Cancer Stem Cells versus Rejuvenation: Nanog is frequently upregulated in cancer stem cells. How can we separate its anti-aging functions from its potential to stimulate or maintain cancer stem cell phenotypes in the aging organism?

239. Nanog safe expression thresholds: What are the critical thresholds for Nanog expression levels and durations in different aged tissues that distinguish beneficial rejuvenation from oncogenic transformation or loss of differentiated identity?

240. Interaction with endogenous Nanog homologs/pseudogenes: How does expression of endogenous Nanog homologs or pseudogenes (e.g., NanogP8), which may be oncogenic, impact the safety and efficacy of therapeutic delivery of Nanog for rejuvenation?

Vitalii Bardichev, [06.05.2025 22:35]
241. Immune response to Nanog-expressing cells: How does the aged immune system perceive cells transiently expressing Nanog? Does Nanog itself have any immunomodulatory or immune-evasive properties?

Translational and therapeutic considerations:

242. Biomarkers of Nanog-specific rejuvenation: Which reliable and specific biomarkers indicate successful and safe Nanog-mediated rejuvenation, as opposed to general pluripotency markers or markers of other reprogramming factors?

243. Synergy with non-pluripotent factors: could the rejuvenation effects of Nanog be enhanced or its risks reduced by combining it with factors not directly involved in pluripotency, such as metabolic modulators, epigenetic drugs (e.g., HDAC inhibitors), or senolytics?

244. Targeting Nanog downstream effectors: could key beneficial downstream pathways activated by Nanog for rejuvenation be identified and targeted with small molecules, bypassing the need for direct gene delivery to Nanog?

245. Nanog for ex vivo rejuvenation protocols: could Nanog be particularly useful in ex vivo rejuvenation protocols for certain cell types (e.g., immune cells, certain progenitor cells) prior to retransplantation, improving their therapeutic potential?

246. Longevity and transgenerational effects (in model organisms): How long do the rejuvenating effects of transient Nanog expression persist, and in model organisms, are there any unexpected (beneficial or detrimental) transgenerational epigenetic effects if germ cells are inadvertently exposed?