https://centre.santafe.edu/complextime/w/index.php?title=Hallmarks_of_Biological_Failure/MorganLevine&feed=atom&action=historyHallmarks of Biological Failure/MorganLevine - Revision history2024-03-28T12:10:53ZRevision history for this page on the wikiMediaWiki 1.35.6https://centre.santafe.edu/complextime/w/index.php?title=Hallmarks_of_Biological_Failure/MorganLevine&diff=4265&oldid=prevMorganLevine at 23:02, April 9, 20192019-04-09T23:02:54Z<p></p>
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<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>* How does this fit in to the findings from heterochronic parabiosis? Would changing the environment of the niche from old to you or vice versa alter 1) clonal hematopoiesis, or 2) probably of neoplastic transformation? What is the impact of HRAS in young versus old environment?</div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>* How does this fit in to the findings from heterochronic parabiosis? Would changing the environment of the niche from old to you or vice versa alter 1) clonal hematopoiesis, or 2) probably of neoplastic transformation? What is the impact of HRAS in young versus old environment?</div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>* Aging may be both the small perturbations to the system and the reaction to perturbations in neighboring systems for which one depends on. With a healthy neighbor idea, a small perturbation may not matter if the interacting system is functioning well, but ass the systems all go down hill together, there will be feedback that will cause an acceleration in the rate of multi-system declines. This may account for why things that change linearly with age, produce exponential morbidity/mortality cures at the level of the population.</div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>* Aging may be both the small perturbations to the system and the reaction to perturbations in neighboring systems for which one depends on. With a healthy neighbor idea, a small perturbation may not matter if the interacting system is functioning well, but ass the systems all go down hill together, there will be feedback that will cause an acceleration in the rate of multi-system declines. This may account for why things that change linearly with age, produce exponential morbidity/mortality cures at the level of the population.</div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins style="font-weight: bold; text-decoration: none;"></ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins style="font-weight: bold; text-decoration: none;">* CR is changes a lot of pathways that together produce both lifespan and health span extension.</ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins style="font-weight: bold; text-decoration: none;">* One can start to map the CR response to systems-level (or network) changes involved in a variety of pathways.</ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins style="font-weight: bold; text-decoration: none;">* Interesting overlap with the genetic architecture of insulin resistance</ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins style="font-weight: bold; text-decoration: none;">* The same pathways that come up in CR are also the ones we are finding relate to the epigenetic clocks in humans. Also evidence that CR decreases mouse epigenetic age.</ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins style="font-weight: bold; text-decoration: none;">* Wells that define healthy vs. sick and transition out of a well depends on depth, curvature, and the size of the fluctuations.</ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins style="font-weight: bold; text-decoration: none;">* A hidden Markov is a good way to model this because the transition to a given well/state depends upon the current state—doesn’t matter how you got there just the parameters above (I would also add that there are likely many well and proximity to a well influences probability of transition). </ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins style="font-weight: bold; text-decoration: none;">* I would ask whether the overall landscape is changing, or whether the available landscape (what is in your vantage point given where you are) is the only thing that changes. If we think of the wells as discrete states, they shouldn’t actually change, just your probability of sampling a given space given your current space will change.</ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins style="font-weight: bold; text-decoration: none;">* Can you also model entropy using these wells? Basically you will have a tendency to move lower in a landscape towards equilibrium and moving uphill requires energy input.</ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins style="font-weight: bold; text-decoration: none;">* Does it make sense to consider single-cell data and investigate the probability distributions of having a multi-dimensional profile as a function of age (could use something like Mahalanobis distance).</ins></div></td></tr>
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</table>MorganLevinehttps://centre.santafe.edu/complextime/w/index.php?title=Hallmarks_of_Biological_Failure/MorganLevine&diff=4248&oldid=prevMorganLevine at 22:52, April 9, 20192019-04-09T22:52:17Z<p></p>
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<td colspan="2" style="background-color: #fff; color: #202122; text-align: center;">Revision as of 22:52, April 9, 2019</td>
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<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>{{Attendee note</div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>{{Attendee note</div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div>|Post-meeting summary=<del class="diffchange diffchange-inline">I think one </del>of <del class="diffchange diffchange-inline">the most interesting themes for me was the idea </del>that aging <del class="diffchange diffchange-inline">may be less due to accumulation </del>of <del class="diffchange diffchange-inline">damage</del>, <del class="diffchange diffchange-inline">but rather</del>, <del class="diffchange diffchange-inline">may reflect maladaptive responses to </del>the <del class="diffchange diffchange-inline">aged</del>-<del class="diffchange diffchange-inline">system or "aged environment"</del>. <del class="diffchange diffchange-inline">The idea that there </del>may be <del class="diffchange diffchange-inline">multiple interacting complex systems that are designed (or evolved) to function in tandem (under certain innate environmental conditions set by neighboring/interacting systems). However with aging, </del>the <del class="diffchange diffchange-inline">dysregulation that increases as a result </del>of <del class="diffchange diffchange-inline">small perturbations in networks</del>/<del class="diffchange diffchange-inline">systems (perceived as intrinsic </del>environment <del class="diffchange diffchange-inline">changes) may acerbate aging </del>in <del class="diffchange diffchange-inline">connect systems leading </del>to <del class="diffchange diffchange-inline">an accelerated rate of failure sue to feedback. This also makes sense in terms of antagonistic pleiotropy--in a young system certain things are advantageous, yet as other systems fail, they may become maladaptive. This also is interesting in </del>the <del class="diffchange diffchange-inline">context of </del>heterochronic parabiosis <del class="diffchange diffchange-inline">in that exposure </del>of <del class="diffchange diffchange-inline">an </del>old <del class="diffchange diffchange-inline">animal </del>to <del class="diffchange diffchange-inline">a young system </del>or vice versa is <del class="diffchange diffchange-inline">advantageous/maladaptive. </del></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div>|Post-meeting summary=<ins class="diffchange diffchange-inline">* Considerations </ins>of <ins class="diffchange diffchange-inline">time-scales. Where/how is time encoded? </ins></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> </div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins class="diffchange diffchange-inline">* With time, new structures emerge, network connectivity changes</ins></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div><del class="diffchange diffchange-inline">The other theme I found very interesting was </del>the <del class="diffchange diffchange-inline">idea </del>of <del class="diffchange diffchange-inline">modeling aging </del>in the <del class="diffchange diffchange-inline">context of landscapes/wells that can be used </del>to <del class="diffchange diffchange-inline">define </del>the <del class="diffchange diffchange-inline">state of </del>the <del class="diffchange diffchange-inline">organisms/system</del>. <del class="diffchange diffchange-inline">Over time</del>, the system <del class="diffchange diffchange-inline">will randomly sample other landscapes</del>, <del class="diffchange diffchange-inline">yet have a propensity to move towards lower towards equilibrium. For </del>the <del class="diffchange diffchange-inline">system</del>, there <del class="diffchange diffchange-inline">may </del>be <del class="diffchange diffchange-inline">a certain depth </del>that <del class="diffchange diffchange-inline">corresponds to failure, which hypothetically could be reached via a multitude </del>of <del class="diffchange diffchange-inline">paths</del>. <del class="diffchange diffchange-inline">Finally</del>, <del class="diffchange diffchange-inline">energy allocation or perturbation is needed to get over a hump, particularly to go back up to a higher </del>level <del class="diffchange diffchange-inline">(further from equilibrium)</del>.</div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins class="diffchange diffchange-inline">* Can hyperactivity </ins>that <ins class="diffchange diffchange-inline">optimizes growth and development contribute to </ins>aging <ins class="diffchange diffchange-inline">(antagonistic pleiotropy)</ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins class="diffchange diffchange-inline">* Peto’s paradox—what things besides the number of cells, which should influence probably </ins>of <ins class="diffchange diffchange-inline">neoplastic transformation</ins>, <ins class="diffchange diffchange-inline">confer differences in species-level cancer risk?</ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins class="diffchange diffchange-inline">* Only the intercept</ins>, <ins class="diffchange diffchange-inline">not the slope for </ins>the <ins class="diffchange diffchange-inline">age</ins>-<ins class="diffchange diffchange-inline">specific rates of lung cancer differ between smokers and never smokers</ins>.</div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins class="diffchange diffchange-inline">* May not be intrinsic damage accumulation and instead </ins>may be the <ins class="diffchange diffchange-inline">difference </ins>of <ins class="diffchange diffchange-inline">the “aged” vs. young environment which differentially selects for oncogenesis</ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins class="diffchange diffchange-inline">* Clonal hematopoiesis could be facilitated</ins>/<ins class="diffchange diffchange-inline">accelerated by the old versus young </ins>environment<ins class="diffchange diffchange-inline">?</ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins class="diffchange diffchange-inline">* How does this fit </ins>in to the <ins class="diffchange diffchange-inline">findings from </ins>heterochronic parabiosis<ins class="diffchange diffchange-inline">? Would changing the environment </ins>of <ins class="diffchange diffchange-inline">the niche from </ins>old to <ins class="diffchange diffchange-inline">you </ins>or vice versa <ins class="diffchange diffchange-inline">alter 1) clonal hematopoiesis, or 2) probably of neoplastic transformation? What </ins>is the <ins class="diffchange diffchange-inline">impact </ins>of <ins class="diffchange diffchange-inline">HRAS </ins>in <ins class="diffchange diffchange-inline">young versus old environment?</ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins class="diffchange diffchange-inline">* Aging may be both </ins>the <ins class="diffchange diffchange-inline">small perturbations </ins>to the <ins class="diffchange diffchange-inline">system and </ins>the <ins class="diffchange diffchange-inline">reaction to perturbations in neighboring systems for which one depends on</ins>.<ins class="diffchange diffchange-inline"> With a healthy neighbor idea</ins>, <ins class="diffchange diffchange-inline">a small perturbation may not matter if </ins>the <ins class="diffchange diffchange-inline">interacting </ins>system <ins class="diffchange diffchange-inline">is functioning well</ins>, <ins class="diffchange diffchange-inline">but ass </ins>the <ins class="diffchange diffchange-inline">systems all go down hill together</ins>, there <ins class="diffchange diffchange-inline">will </ins>be <ins class="diffchange diffchange-inline">feedback </ins>that <ins class="diffchange diffchange-inline">will cause an acceleration in the rate </ins>of <ins class="diffchange diffchange-inline">multi-system declines</ins>. <ins class="diffchange diffchange-inline">This may account for why things that change linearly with age</ins>, <ins class="diffchange diffchange-inline">produce exponential morbidity/mortality cures at the </ins>level <ins class="diffchange diffchange-inline">of the population</ins>.</div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>}}</div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div>}}</div></td></tr>
</table>MorganLevinehttps://centre.santafe.edu/complextime/w/index.php?title=Hallmarks_of_Biological_Failure/MorganLevine&diff=4197&oldid=prevMorganLevine: Created page with "{{Attendee note |Post-meeting summary=I think one of the most interesting themes for me was the idea that aging may be less due to accumulation of damage, but rather, may refl..."2019-04-08T22:59:26Z<p>Created page with "{{Attendee note |Post-meeting summary=I think one of the most interesting themes for me was the idea that aging may be less due to accumulation of damage, but rather, may refl..."</p>
<p><b>New page</b></p><div>{{Attendee note<br />
|Post-meeting summary=I think one of the most interesting themes for me was the idea that aging may be less due to accumulation of damage, but rather, may reflect maladaptive responses to the aged-system or "aged environment". The idea that there may be multiple interacting complex systems that are designed (or evolved) to function in tandem (under certain innate environmental conditions set by neighboring/interacting systems). However with aging, the dysregulation that increases as a result of small perturbations in networks/systems (perceived as intrinsic environment changes) may acerbate aging in connect systems leading to an accelerated rate of failure sue to feedback. This also makes sense in terms of antagonistic pleiotropy--in a young system certain things are advantageous, yet as other systems fail, they may become maladaptive. This also is interesting in the context of heterochronic parabiosis in that exposure of an old animal to a young system or vice versa is advantageous/maladaptive. <br />
<br />
The other theme I found very interesting was the idea of modeling aging in the context of landscapes/wells that can be used to define the state of the organisms/system. Over time, the system will randomly sample other landscapes, yet have a propensity to move towards lower towards equilibrium. For the system, there may be a certain depth that corresponds to failure, which hypothetically could be reached via a multitude of paths. Finally, energy allocation or perturbation is needed to get over a hump, particularly to go back up to a higher level (further from equilibrium).<br />
}}</div>MorganLevine