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Difference between revisions of "Hallmarks of Biological Failure/JamesDeGregori"

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|Post-meeting summary=A system can take a certain # of hits. A lot of failures are linear with age ''on a log scale''. Why?  Resiliency? Due to redundancy? What explains variance in a population? Natural selection has acted to limit physiological decline to the point that maximizes reproductive success (balanced against costs).  So risk of physiological failure are not zero during reproductive years, but are minimized, certainly relative to competing risks for most of our (or other animal's) evolutionary history.  
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|Post-meeting summary=''Overall thoughts: A system can take a certain # of hits. A lot of failures are linear with age on a log scale. Why?  Resiliency? Due to redundancy? What explains variance in a population? Natural selection has acted to limit physiological decline to the point that maximizes reproductive success (balanced against costs).  So risk of physiological failure are not zero during reproductive years, but are minimized, certainly relative to competing risks for most of our (or other animal's) evolutionary history.''
  
 
<u>Bernie Crespi</u> presented on how selection works stronger on the weaker components. Slow, invisible weaknesses increase over time. Can engender exponentiality of decay. Or is it that damage and mutations accumulate over time. Risk of failure is related to the degree of complexity in a system, and tightness of coupling between components. For example, power grids are tightly coupled but not hugely complex.  Aircraft are both coupled and complex. Mental disorders represent alternative attractors in a highly coupled system. For immune system, autoimmunity, chronic inflammation, cytokine storms represent alternative attractors potentiated by tight coupling. Both can have diseases associated with over-defense.  Both do not trade off well with other systems. Immune system is under greater positive selection, relative to brain system which is more stabilizing. ''I would ask how the failure rate of systems, complex or not, is impacted by environmental disconnects.  For example, failures in the immune system (like autoimmunity) may be common today, but were not so common in ancestral times (re. hygiene hypothesis).''   
 
<u>Bernie Crespi</u> presented on how selection works stronger on the weaker components. Slow, invisible weaknesses increase over time. Can engender exponentiality of decay. Or is it that damage and mutations accumulate over time. Risk of failure is related to the degree of complexity in a system, and tightness of coupling between components. For example, power grids are tightly coupled but not hugely complex.  Aircraft are both coupled and complex. Mental disorders represent alternative attractors in a highly coupled system. For immune system, autoimmunity, chronic inflammation, cytokine storms represent alternative attractors potentiated by tight coupling. Both can have diseases associated with over-defense.  Both do not trade off well with other systems. Immune system is under greater positive selection, relative to brain system which is more stabilizing. ''I would ask how the failure rate of systems, complex or not, is impacted by environmental disconnects.  For example, failures in the immune system (like autoimmunity) may be common today, but were not so common in ancestral times (re. hygiene hypothesis).''   
  
 
<u>Dario Valenzano</u> described how relaxed selection shapes the rate of aging across species. Killifish get tons of cancer late in life; almost all die with cancer. Not clear if they die of cancer, just with cancer. Lives in area where water is available for a few months of the year. Have drought resistant embryos. Can desiccate embryos. Hatch when rains. 5-6 rounds of spawning. Wetter areas – longer lives. Did a lot of genetic mapping. QTL of longevity. Can do crosses and single alleles can have big effects. Show heart, skeletal, and many other aging phenotypes. See evolution of life spans multiple times across killifish species. So can filter out phylogenetic relatedness. Short lived (annual) species have a larger genome mostly due to expansion of transposable elements and introns. A lot of LINE expansion. Probably due to reduced purifying selection. Much more of coding sequence is under purifying selection in non-annuals. Populations evolving in dry environments have smaller Ne - even within the same species found in dry and wet environments. See expansion of mitochondrial genomes in annuals too, with a higher mutation rate (again consistent with weakened selection). In fact, the mitochondrial polymerase is more error prone. ''The question that I would raise is WHY is selection weakened?  Clearly, a smaller Ne would do this, but why is there a smaller Ne?  Is there a bottleneck with each season where only a small fraction of dried embryos survive and reproduce again?''
 
<u>Dario Valenzano</u> described how relaxed selection shapes the rate of aging across species. Killifish get tons of cancer late in life; almost all die with cancer. Not clear if they die of cancer, just with cancer. Lives in area where water is available for a few months of the year. Have drought resistant embryos. Can desiccate embryos. Hatch when rains. 5-6 rounds of spawning. Wetter areas – longer lives. Did a lot of genetic mapping. QTL of longevity. Can do crosses and single alleles can have big effects. Show heart, skeletal, and many other aging phenotypes. See evolution of life spans multiple times across killifish species. So can filter out phylogenetic relatedness. Short lived (annual) species have a larger genome mostly due to expansion of transposable elements and introns. A lot of LINE expansion. Probably due to reduced purifying selection. Much more of coding sequence is under purifying selection in non-annuals. Populations evolving in dry environments have smaller Ne - even within the same species found in dry and wet environments. See expansion of mitochondrial genomes in annuals too, with a higher mutation rate (again consistent with weakened selection). In fact, the mitochondrial polymerase is more error prone. ''The question that I would raise is WHY is selection weakened?  Clearly, a smaller Ne would do this, but why is there a smaller Ne?  Is there a bottleneck with each season where only a small fraction of dried embryos survive and reproduce again?''
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<u>Shripad Tuljapurkar</u> – As we get older, get more response to similar challenges. ''My thoughts - but do we?  Or do we simply return to homeostasis more poorly? In fact, some times responses are exaggerated and prolonged (such as with inflammation) in old animals.'' Escape from “well” for a phenotype is dependent on depth of well, size of fluctuations, and multidem space. Old age involves shallowing of healthy well and deepening of sick well. ''The well may also be broader, with a greater diversity of phenotypes (cellular) for the same cell type.  Relaxed purifying selection, as well as epigenetic drift, could contribute to this.''
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 +
<u>Sabrina Spencer</u> discussed how replication stress and DNA damages induces p21 in mother, leading to increased p21 high offspring which stay quiescent longer.  And these cells are stress resistant (survive better D dam). See much less pausing at early passages of foreskin fibroblasts relative to late.  ''It will be interesting to see how these dynamics contribute to tissue aging.  Also, in a competitive tissue do these same cells with DNA damage get purged? There is evidence from flies and mice that that damaged cells can be pushed out by healthy neighbors.''
 
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Revision as of 22:57, April 8, 2019

Notes by user James DeGregori (CU Denver) for Hallmarks of Biological Failure

Post-meeting Reflection

1+ paragraphs on any combination of the following:

  • Presentation highlights
  • Open questions that came up
  • How your perspective changed
  • Impact on your own work
  • e.g. the discussion on [A] that we are having reminds me of [B] conference/[C] initiative/[D] funding call-for-proposal/[E] research group

Overall thoughts: A system can take a certain # of hits. A lot of failures are linear with age on a log scale. Why?  Resiliency? Due to redundancy? What explains variance in a population? Natural selection has acted to limit physiological decline to the point that maximizes reproductive success (balanced against costs). So risk of physiological failure are not zero during reproductive years, but are minimized, certainly relative to competing risks for most of our (or other animal's) evolutionary history.

Bernie Crespi presented on how selection works stronger on the weaker components. Slow, invisible weaknesses increase over time. Can engender exponentiality of decay. Or is it that damage and mutations accumulate over time. Risk of failure is related to the degree of complexity in a system, and tightness of coupling between components. For example, power grids are tightly coupled but not hugely complex.  Aircraft are both coupled and complex. Mental disorders represent alternative attractors in a highly coupled system. For immune system, autoimmunity, chronic inflammation, cytokine storms represent alternative attractors potentiated by tight coupling. Both can have diseases associated with over-defense.  Both do not trade off well with other systems. Immune system is under greater positive selection, relative to brain system which is more stabilizing. I would ask how the failure rate of systems, complex or not, is impacted by environmental disconnects. For example, failures in the immune system (like autoimmunity) may be common today, but were not so common in ancestral times (re. hygiene hypothesis).

Dario Valenzano described how relaxed selection shapes the rate of aging across species. Killifish get tons of cancer late in life; almost all die with cancer. Not clear if they die of cancer, just with cancer. Lives in area where water is available for a few months of the year. Have drought resistant embryos. Can desiccate embryos. Hatch when rains. 5-6 rounds of spawning. Wetter areas – longer lives. Did a lot of genetic mapping. QTL of longevity. Can do crosses and single alleles can have big effects. Show heart, skeletal, and many other aging phenotypes. See evolution of life spans multiple times across killifish species. So can filter out phylogenetic relatedness. Short lived (annual) species have a larger genome mostly due to expansion of transposable elements and introns. A lot of LINE expansion. Probably due to reduced purifying selection. Much more of coding sequence is under purifying selection in non-annuals. Populations evolving in dry environments have smaller Ne - even within the same species found in dry and wet environments. See expansion of mitochondrial genomes in annuals too, with a higher mutation rate (again consistent with weakened selection). In fact, the mitochondrial polymerase is more error prone. The question that I would raise is WHY is selection weakened? Clearly, a smaller Ne would do this, but why is there a smaller Ne? Is there a bottleneck with each season where only a small fraction of dried embryos survive and reproduce again?

Shripad Tuljapurkar – As we get older, get more response to similar challenges. My thoughts - but do we? Or do we simply return to homeostasis more poorly? In fact, some times responses are exaggerated and prolonged (such as with inflammation) in old animals. Escape from “well” for a phenotype is dependent on depth of well, size of fluctuations, and multidem space. Old age involves shallowing of healthy well and deepening of sick well. The well may also be broader, with a greater diversity of phenotypes (cellular) for the same cell type. Relaxed purifying selection, as well as epigenetic drift, could contribute to this.

Sabrina Spencer discussed how replication stress and DNA damages induces p21 in mother, leading to increased p21 high offspring which stay quiescent longer.  And these cells are stress resistant (survive better D dam). See much less pausing at early passages of foreskin fibroblasts relative to late.  It will be interesting to see how these dynamics contribute to tissue aging. Also, in a competitive tissue do these same cells with DNA damage get purged? There is evidence from flies and mice that that damaged cells can be pushed out by healthy neighbors.

Reference material notes

Some examples:

  • Here is [A] database on [B] that I pull data from to do [C] analysis that might be of interest to this group (insert link).
  • Here is a free tool for calculating [ABC] (insert link)
  • This painting/sculpture/forms of artwork is emblematic to our discussion on [X]!
  • Schwartz et al. 2017 offers a review on [ABC] migration as relate to climatic factors (add the reference as well).

Reference Materials