Hallmarks of Biological Failure/RozalynAnderson

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Notes by user Rozalyn Anderson (Univ. Wisconsin) 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

A theme that I see across the talks and in the discussion is the issue of complexity and how integrity of complex systems is lost with age and how it might be retained to impinge on health and resilience.

The idea of the adaptive landscape is very useful as is the idea of tipping point - i particularly like the idea of aging as a series of transitions where the path taken dictates the possibilities open for the future

Hochberg: Concepts that caught my attention, as a function of age is loss of resilience equally felt through the lifespan ie young v old? Also Diverse/idiosynchratic networks – how should models be informed. The idea of hierarchies of regulatory or adaptive nodes is interesting but I wonder do we know that there are grades of nodes in the first place, if there are how do we find them?

Crespi : Biological Risk Matrix… coupling versus complexity. I had difficulty with this idea because the systems were assigned importance but it wasn't clear to me what the basis for those assignations was. I have viewed the organ systems as different but inseparable pieces of the organism as a whole. I do like the idea of viewing the aging of specific processes in terms of trade-offs - I wonder about the inbuilt redundancy of systems and think we could consider the possibility that age-induced adaptions might just as well be beneficial - ie tailored to the prevailing internal environment or the current disposition of regulatory nodes.

Valenzano: The fact that ecology predicts genome size was super interesting and that the expansion is explained by transposons! I also loved the idea that the long-lived species had more emphasis on positive/purifying selection and the short-lived species had more evidence of the relaxed selection. These are an amazingly useful species for the interactions of genetics, environment - the exposome!

Di Gregorio: Among cancers age dependence in risk is shared despite differences in etiology and mechanisms of tumorigenesis and differences in the stem cell pools that these cancers arise from. All map to a common cancer curve – incidence as a function of age all lie right on top of each other. This nicely captures the idea that aging creates a ubiquitous risk increase for cancer incidence. Metastasis – moving from the environment where the tumorigenesis initiated – giant hurdle for success but likely to be huge number of cells that slough off. Idea that youth is associated with “Healthy Neighbors” proximal to the initiating cancer cells. Aging is not just accumulation of mutation: idea that the tissue changes create the promiscuous setting. Essentially: the behavior of a single mutation is not equivalent in young and old environments

Tuljapurkar: Response to challenge changes with age – makes the case that the amplitude of the response in young is muted and un-muted and over-amplified in aged, although I would think of it as a disconnection in the response whether that be under or over reactionary. I was very taken with the idea that response to a challenge could push you out of the equilibrium space and into a different state altogether & that you would need to consider the following: Depth of well; curvature of the well; size of the fluctuations.

Spencer: very interesting model for thinking about non-genetic sources of heterogeneity looking at individual cells through the lens of Proliferating v quiescence as a cell state.  Spontaneous heterogeneity in asynchronously cycling cells used to identify key nodes in dictating the pace of cell cycle - really nice cell biology and time lapse imaging to uncover CDK2, p21, and stalled forks in the mechanisms. Interesting observation that Mothers pass damage on to the daughters so that the intent to enter quiescence already established in G2 of the mother. Genetic approaches to manipulate CDK2/p21 show that the slow cycling cells have higher stress tolerance – If you force CDK2 in the pausers have a fitness deficit - I wonder though if this is just because cells not ready for division were forced into it creating a vulnerability to stress rather than exposing a beneficial role for the pause.

Natterson-Horowitz: Using examples from different species the relative balance of sympathetic/parasympahtetic v vagal response to stress was explored. High-adrenergic events: eg sudden cardiac, death cardiomyopathy refelctive of a dysregulation of autonomic balanceTonic immobility in response to attach – seen in many different species. Alarm bradycardia is primarily a juvenile response. Not called syncope (because not people) but it sure looks like it. As the animals transition to adulthood they swap over to the sympathetic/parasympathetic response. I do wonder how this is coordinated and communicated with maturation - could there be a signal to indicate that a critical physical threshold had been reached for example, like myokines even? I like the idea that with age there may be a disconnect where there is a loss of the ability to toggle between sympathetic/parasympathetic and vagal responses☂Open questions are whether early experiences inform future balance in terms of response to trauma, Can we build predictive models?

OPEN DISCUSSION: Identified 3 themes: 1. Vulnerability with age, 2. Variance among individuals, 3. Complexity

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