Hallmarks of Biological Failure/DarioValenzano
Notes by user Dario Riccardo Valenzano (Max Planck) for Hallmarks of Biological Failure
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
DPromislow: Evolution shapes function and failure. Three dimensional space: Failure, Function and Evolution.
Main question: why do different agents age at different rates (faster, slower?)
MHochberg: Function criticality, aging and resilience. Coupling mechanisms of adaptation and aging. Wait, what are we referring to here for adaptation?
Is it evolutionary Explain this! Oncogenic mutations in young healthy stem cell
populations typically reduce cellular fitness.
Peto's paradox: large and long-lived animals do not develop more
Cancers requiring different numbers of driver mutations and
originating from vastly differently organized stem cell pools
demonstrate very similar age-dependent incidence.
Adaptive oncogenesis: we evolved stem cells that are well adapted to
the tissue niche. Stabilised selection for the evolved type. This is
more powerful than avoiding mutations. Stem cells would be adapting to
q: does it mean that changing the tissue environment you would lead
stem cells (cancer) to evolved towards optimality in the "healthy"
q2: how about metastasis? do they evolve new-niche specific
variations? or physiological adaptations?
Conserved pathways responsive to caloric restriction, across tissues.
Chronic low-level mitochondrial activation in cells. Mito regulator
PGC 1A (expressed to 1.5X, similarly to CR tissues). Super cool!
- Frailty and disability: transitions
- Post-reproduction lifespan
u(a, H) < u(a, S)
u: death rate
Recovery becomes harder as we age.
Decline in homeostasis with aging.
Potential well model (similar to fitness lanscapes)
Escape from potential well. Fluctuations depend on well depth, curvature of well and size of fluctuation. It's a multidimensional space.
Prob (H --> Ha)
Prob(S --> Sa)
As we age, the profile of the H and S well changes, making it harder for the ball to escape from the S well.
Longitudinal data on health, frailty, morbidity. HMM drive transition states. (Aging studies, Framingham, HRS, ...).
borrowing Hamilton's fitness (grandmother effect, old men, learning, transfers).
Causes and consequences of non-genetic heterogeneity.
How do cells switch back and forth between quiescence and
proliferation. Shift from G1 towards G0 depends on CDK2 (off). She develops awesome trackers for CDK2. Wow!
Bifurcation in CDK2 activity appears in many cell types.
p21 inhibits CDK2. p21 -\- remove the bifurcation, leading to proliferation
only, no quiescence. Many quiescent cells have DNA lesions. Mothers of
quiescent daughters have a longer cell cycle. Daughter quiescence is
decided in the mother's G2 phase. Mother cells pass DNA damage to
their offspring cells (i.e. do not retain the damage).
CDK2low state fortifies cell lineage against stress.
Cardiovascular disease in humans, non-human primates, lions sympathetic and parasympathetic system.
Sudden cardiac death (SCD), "Tahatsubo" cardiomyopathy.
High adrenergic events. Sympathetic responses are flight and fight. Parasympathetic responses are opposite: faint, shit yourself, etc.
Fainting: vasovagal syncope (VVS), due to underprofusion of the brain.
VVS: paradoxical bradycardia has developmental characteristics: depends by the age of first fainting.
Alarm bradycardia is preferentially a juvenile phenotype.
Early life events: shaping autonomic nervous system for later events.
Reference material notes
- 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).
|Title||Author name||Source name||Year||Citation count From Scopus. Refreshed every 5 days.||Page views||Related file|
|In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming Cellular reprogramming by transient expression of Yamanaka factors ameliorates age-associated symptoms, prolongs lifespan in progeroid mice, and improves tissue homeostasis in older||Cell||2016||0||3|
|Demography of dietary restriction and death in Drosophila||Science||2003||0||1|