Longevity Questions

Pathways to New Therapies:

Can the answers to the previous questions suggest fundamentally new approaches to treatment aimed at the root cause? For example:

122. Targeted correction of TGF-β signaling (or other pathways)?

123. Using RNA therapy to suppress expression of the mutant allele?

124. Developing "pharmacological chaperones" to improve folding and secretion of mutant proteins?

125. Stimulating compensatory mechanisms or alternative pathways of matrix assembly?

126. Gene therapy with delivery of a normal copy of the gene?

Evolutionary "Price" of Difficulty:

127. Are these diseases a kind of "price" for the evolutionary complexity of the structure and function of the extracellular matrix in vertebrates?

Transhumanism in a Distant City, [05.05.2025 04:38]
To understand how exactly fibroblast signaling changes with age in the context of collagen synthesis, especially through the TGF-β/Smad and vitamin C-dependent pathways, we need to answer the following, more detailed scientific questions:

General changes in signaling capacity of aging fibroblasts:

Receptors and ligands:

128. How does the number and functional activity of receptors for TGF-β and other growth factors (e.g., FGF, IGF) on the surface of aging fibroblasts change?

129. Do cells become less "sensitive" to stimulating signals?

130. Does the local availability or activity of the ligands themselves (e.g., TGF-β) change in the microenvironment of aging skin?

Intracellular signaling:

131. Is the efficiency of downstream signaling from an activated receptor reduced? For example, is phosphorylation and nuclear translocation of key proteins such as Smad2/3 impaired?

132. Is the activity or abundance of kinases and phosphatases that regulate these signaling pathways altered in senescent cells?

133. Is there increased "noise" or non-specific activation of pathways in senescent cells that may interfere with accurate response to the collagen synthesis signal?

Gene regulation:

134. How does the epigenetic landscape (DNA methylation, histone modifications) change in genes encoding pathway components (receptors, Smads) and collagens themselves (COL1A1, COL1A2, COL3A1) in senescent fibroblasts? Do these genes "go silent"?

135. Are the activities of key transcription factors (besides Smads, e.g. AP-1) that are required for activation of collagen genes altered, and how do they cross-talk with Smads in aged cells?

TGF-β/Smad pathway specificity:

Signaling balance:

136. Are inhibitory Smads (Smad6/7) that counteract the TGF-β signal increased in expression or activity with age?

137. How does the TGF-β/Smad pathway interact with other signaling cascades (e.g. Wnt, MAPK) that may also influence collagen synthesis, and how does this cross-talk change with age?

Specificity of Vitamin C-Dependent Pathways:

Vitamin C Transport and Availability:

138. Is the expression or function of vitamin C transporters (SVCT1, SVCT2) reduced on the membrane of aging fibroblasts?

139. Is sufficient vitamin C delivered to the cell?

140. What is the actual intracellular concentration of vitamin C in fibroblasts from aged skin compared to young skin?

Enzyme activity:

141. Is the activity of prolyl and lysyl hydroxylases (key enzymes in collagen maturation that require vitamin C as a cofactor) reduced in aging cells, even in the presence of vitamin C?

142. Is this due to changes in the enzymes themselves or in the availability of other cofactors (e.g., iron)?

143. How do age-related changes affect the regulatory functions of vitamin C related to gene expression (e.g., through effects on TET enzymes and DNA demethylation)?

Influence of cellular state and microenvironment:

Metabolism and energy:

144. How do changes in cellular metabolism (e.g., decreased mitochondrial function, changes in AMPK/mTOR pathways) in aging fibroblasts affect their ability to sustain the energy-consuming process of collagen synthesis and secretion in response to signals?

145. How does the accumulation of damage (e.g., oxidative stress, DNA damage) in senescent fibroblasts affect the integrity and fidelity of their signaling systems?

146. How do components of the senescent matrix (fragmented collagen, AGEs) and factors secreted by senescent cells (SASP) directly influence collagen synthesis signaling pathways in adjacent, still functional fibroblasts?