Perpetual Prompt ♾️, [08.05.2025 20:36]
481. What are the molecular mechanisms by which chronic suppression of the GnRH signal affects the rate of epigenetic aging in primates, and can these effects be pharmacologically separated from the secondary suppression of osteogenesis?
482. Is it possible to achieve a partial “rollback” of the hormonal profile to the pre-pubertal level without loss of cognitive functions by modulating the expression of Kiss1/Kiss1r in adult hypothalamic neurons?
483. How does long-term absence of sex steroids affect the repertoire of DNA repair pathways in human somatic tissues, and what gene therapies can compensate for the identified deficiencies?
484. What changes in mitochondrial biogenesis are caused by suppression of the GH/IGF-1 axis during adolescence, and are these changes sufficient to explain the extended lifespan in dwarf models?
485. What minimum estrogen/androgen activity is required to maintain corticohippocampal neuroplasticity at a level that prevents premature cognitive aging?
486. Does chronic administration of GnRH agonists to young adult mice, combined with an intermittent mTORC1 autophagy activator, synergistically extend median lifespan by >50%?
487. Can editing of regulatory elements in the aromatase (CYP19A1) gene achieve tissue-specific suppression of estrogen synthesis such that bone mass is preserved and systemic aging is delayed?
488. What are the long-term effects of pharmacological pubertal blockade on human hematopoietic stem cell clones and their susceptibility to age-associated mutations in DNMT3A, TET2, ASXL1?
489. Is there a “critical window” within which sex hormone suppression maximizes lifespan in mammals, and what determines it at the transcriptome level?
490. How do changes in circulating FGF-21 levels following pubertal delay affect systemic metabolism and is this reproducible in humans by hormone therapy?
491. Which microRNA signatures of suppressed puberty correlate with reduced biological age velocity and may serve as therapeutic mimetics?
492. Can a chronopharmacological regimen of alternating GnRH agonists and antagonists prevent the development of osteopenia during long-term sex hormone suppression?
493. How does long-term estrogen deficiency affect lymphoid clonal drift and the risk of immunosenescence, and can it be compensated for by IL-7 or FOXO1-targeted therapy?
494. What changes in the composition of the gut microbiome occur during pharmacological delay of puberty and how do they mediate the anti-inflammatory effect in long-lived models?
495. What is the minimum dose of recombinase-mediated CYP17A1 gene inhibition required to slow aging without complete loss of DHEA and corticosteroid synthesis?
496. Can CRISPR-off be used to permanently reduce insulin receptor expression in Kiss neurons of adult mice and extend their lifespan without causing diabetogenic effects in the periphery?
497. How does delayed puberty affect the dynamics of TERT promoter methylation in somatic tissues and the associated telomerase activity?
498. To what extent is the accumulation of somatic mutations in rapidly proliferating epithelia slowed down by chronic suppression of sex hormones in animal models?
499. Is it possible to create a biocompatible implant with controlled release of GnRH analogues for 10 years, and how predictably will it maintain subpubertal LH/FSH levels in humans?
500. How does combination therapy with low doses of estrogens and senolytics (e.g., dasatinib + quercetin) affect the premature aging phenotype in suppressed puberty?
501. Which epigenetic clocks are most sensitive to artificial “freezing” of puberty, and how do these clocks correlate with future somatic pathology?
502. How does sexual deprivation during adolescence affect the formation of matrix-attached cells in the thymus and subsequent thymus involution in adults?
Perpetual Prompt ♾️, [08.05.2025 20:36]
503. Did combined GnRH blockade and mTORC1 inhibition during the critical growth period in mice extend maximum lifespan beyond 60 months?
504. What is the role of NAD⁺/SIRT1 signaling in pubertal delay, and can supplementation with NAD⁺ precursors enhance the anti-aging benefits of hormonal suppression without adding cancer risk?
505. Is it possible to activate the neoteny program in adult cardiomyocytes by suppressing puberty and thereby restore their regenerative potential after a heart attack?
506. How does chronic low-level testosterone suppression in men affect the risk of sarcopenia and can it be mitigated by periodic courses of SARMs without discontinuing the main regimen?
507. What are the long-term epigenomic consequences of clinical protocols for adolescent gender therapy (GnRH-agonists±analogous hormones) on the rate of aging and health biomarkers?
508. Is it possible to develop a “smart” delivery of anti-Gnrh siRNA to the hypothalamus using AAV-PHP.eB viral vectors that ensures reversibility of the effect and minimizes systemic side effects?
509. What changes in the plasma metabolome (SCFA, spermidine, ketones) correlate with maximal life extension with delayed puberty and can serve as surrogate endpoints in clinical trials?
510. How does the combination of late but unsuppressed puberty with cyclic use of GH signaling inhibitors (pegvisoman) affect the likelihood of reaching 120+ years and what biomarkers predict the success of the regimen?