Longevity Questions

Transhumanism in a Distant City, [03.05.2025 08:29]
Studying inherited diseases such as Marfan syndrome (MFS) and Cutis Laxa (CL) raises many interesting and challenging questions that go beyond simple descriptions of symptoms and genetics. Here are some of them:

The Riddle of Variability:

102. Why do the clinical manifestations of MFS and CL vary so much even among family members with the same mutation?

103. What genetic factors (modifier genes), epigenetic changes, or environmental factors determine whether a patient will develop a life-threatening aortic aneurysm or only mild skeletal changes?

Tissue Specificity of Lesion:

104. Why does MFS primarily affect the aorta, eyes, and skeleton, while CL primarily affects the skin, lungs, and vessels (often with tortuosity)? After all, fibrillin-1 and elastin are present in many tissues.

105. Is this due to different intensities of mechanical stress, different rates of matrix turnover in these tissues, or the presence of tissue-specific protein isoforms or their interaction partners?

The Role of Signaling Pathways (Beyond TGF-β):

106. In addition to TGF-β dysregulation in MFS, what other intracellular and intercellular signaling pathways are disrupted by defects in fibrillin-1 or elastin assembly components?

107. How do these disruptions contribute to specific pathologies (e.g., bone changes, heart valves)?

108. Is disrupted signaling also a key issue in Cutis Laxa?

Molecular Mechanism of Dominance:

109. What is the precise mechanism in dominant forms (MFS, ADCL)?

110. Is it a simple lack of half of the normal protein (haploinsufficiency)?
Or does the mutant protein actively interfere with the normal protein and the assembly of the entire structure (dominant-negative effect)?

111. How much does it depend on the specific type of mutation (missense, nonsense, frameshift)?

Breakdown points in Elastin Assembly (CL):

112. With mutations in the genes responsible for elastin assembly (FBLN4, FBLN5, LTBP4), at which molecular stage (secretion of tropoelastin, its binding to chaperones, delivery to microfibrils, cross-linking of LOX) does the "jam" occur?

113. Is it possible to pharmacologically "bypass" this block or enhance alternative assembly pathways?

Why is there no Effective Repair?

114. Why is the adult organism practically unable to compensate for the genetic defect and restore damaged or missing elastic fibers/microfibrils?

115. Are there active mechanisms that suppress elastogenesis in adults, or is it simply the absence of the necessary stimuli and components?

116. Can the defective matrix itself inhibit repair?
Models of Accelerated Matrix Aging?

117. To what extent can MFS and CL be considered as models of accelerated or specific aging of the extracellular matrix?

118. What molecular and structural changes in the tissues of patients with these syndromes resemble age-related changes in healthy people?

119. Can rare variants in the FBN1, ELN, FBLN5 genes, etc. affect the individual rate of matrix aging and the risk of age-related diseases (aneurysms, emphysema, wrinkles)?

Non-Mechanical Functions and Their Dysfunctions:

120. What roles, other than purely mechanical support and elasticity, do fibrillin-1, elastin, and related proteins play (e.g., in cell adhesion, chemotaxis, regulation of protease activity)?

121. How does dysfunction of these "non-obvious" functions contribute to the pathogenesis of MFS and CL?