Longevity Questions

Vitalii Bardichev, [06.05.2025 22:32]
Focus on the let-7 axis and RNA biology:

207. Let-7 independent rejuvenation: to what extent are the longevity-promoting or rejuvenating effects of Lin28 mediated independently of its downregulation of the let-7 microRNA family? What are these alternative RNA targets or mechanisms?

208. Lin28A versus Lin28B specificity: do Lin28A (cytoplasmic) and Lin28B (nuclear/nucleolar) play distinct or synergistic roles in cellular rejuvenation and aging? Could one be more beneficial or safer for longevity interventions?

209. Optimal let-7 silencing for rejuvenation: If let-7 silencing is key, what is the optimal level and duration of silencing required for rejuvenation without triggering side effects such as dedifferentiation or cancer (given that let-7 targets many oncogenes)?

210. Restore youthful splicing patterns: Does Lin28 expression in aged cells restore age-associated aberrant alternative splicing patterns, and if so, which transcripts are most critically affected for rejuvenation?

211. Impact on ribosome biogenesis and translation: How does Lin28, in particular the nucleolar localization of Lin28B, affect ribosome biogenesis and global or specific mRNA translation efficiency in aged cells, and how does this contribute to a youthful phenotype?

Metabolic Reprogramming and Energy:

212. Mechanism of Metabolic Rejuvenation: How specifically does Lin28 enhance glucose metabolism and mitochondrial function in aged cells? Primarily via let-7 targets (such as IGF2BP, Ras, Myc proteins) or other metabolic regulators?

213. Reversal of Age-Related Insulin Resistance: Can Lin28 expression systemically or in specific tissues (e.g., muscle, liver) reverse age-related insulin resistance and improve glucose homeostasis, and what are the molecular pathways?

214. Improved Cellular Energetics: In addition to glucose metabolism, how does Lin28 influence other aspects of cellular energetics in aged cells, such as fatty acid oxidation or nucleotide metabolism, to support rejuvenation?

Tissue repair and regeneration:

215. Unlocking the potential of adult regeneration: Why can Lin28 promote complex tissue regeneration (e.g., fingertips) in young mammals but not typically in adults? Can this block be overcome in older humans to improve repair of trauma or chronic injury?

216. Specific stem cell targets for Lin28-mediated rejuvenation: Which adult stem cell populations (e.g., mesenchymal, satellite, hematopoietic) are most susceptible to Lin28-mediated rejuvenation, and what are the functional implications for tissue health?

217. Lin28 and wound healing in aging skin: Can Lin28 expression accelerate and improve wound healing in aging skin, which is typically slow and prone to scarring, and which cellular players are involved (keratinocytes, fibroblasts, immune cells)?

Safety, tumorigenesis, and systemic effects:

218. Disentangling rejuvenation and tumorigenesis: Given the role of Lin28 as an oncogene in many cancers (often via let-7 downregulation and Myc/Ras activation), how can its anti-aging effects be therapeutically disentangled from its cancer-promoting potential in the aging organism with accumulated mutations?

219. Long-term consequences of transient Lin28 expression: What are the long-term effects (months to years) on cellular identity, function, and cancer risk following a short pulse of Lin28 expression in aged tissues?

220. Dynamics of endogenous Lin28 during aging: How does endogenous Lin28A and Lin28B expression and activity change in different tissues during normal aging, and does its decline contribute to specific age-related pathologies that may be targeted?

221. Non-cell autonomous effects of Lin28: Does expression of Lin28 in certain cells result in the secretion of factors that can rejuvenate nearby or even distant aged cells, and what are these factors?