Theorizing on Gene Network Stability and Aging
Researchers here model the relationship between genetic regulation and aging with an eye towards trying to fit the outcomes in both negligibly senescent and "normally aging" species. It is known that advancing age brings with it epigenetic dysregulation, meaning significant changes in the levels of various proteins produced from their genetic blueprints, and therefore significant changes in cell behavior. Researchers differ on what this means and how close it is to the root causes of aging. In the theories in which aging is an accumulation of damage, then epigenetic changes are far downstream in the chain of cause and consequence; they are a reaction to rising levels of cell and tissue damage.
Several animal species are considered to exhibit what is called negligible senescence, i.e. they do not show signs of functional decline or any increase of mortality with age. Recent studies in naked mole rat and long-lived sea urchins showed that these species do not alter their gene-expression profiles with age as much as other organisms do. This is consistent with exceptional endurance of naked mole rat tissues to various genotoxic stresses. We conjectured, therefore, that the lifelong transcriptional stability of an organism may be a key determinant of longevity.We analyzed the stability of a simple genetic-network model and found that under most common circumstances, such a gene network is inherently unstable. Over a time it undergoes an exponential accumulation of gene-regulation deviations leading to death. However, should the repair systems be sufficiently effective, the gene network can stabilize so that gene damage remains constrained along with mortality of the organism. We investigate the relationship between stress-resistance and aging and suggest that the unstable regime may provide a mathematical basis for the Gompertz "law" of aging in many species. At the same time, this model accounts for the apparently age-independent mortality observed in some exceptionally long-lived animals.
I don't really see any evidence for supposing that genetic instability is just "downstream secondary damage" from the supposed SENS 7 classes of damage. Why can't it be a primary class of damage. Is the SENS foundation exhibiting wishful thinking by disregarding this as a class of damage that must be fixed... because doing so is almost impossible?
Jim, it's explained here: http://www.sens.org/research/introduction-to-sens-research/cancerous-cells
Basically, (epi)mutations that don't produce cancer don't matter for current lifespans. Maybe they need to be addressed by SENS 2.0 or later iterations of the SENS program.
Considering a lot of epigenetic changes to gene expression are from changes in telomere length, DNAm changes and Histone coding changes I would say they are a pretty huge part of aging as they alter the system so utterly and change how the system deals with damage and repairs itself. Hardly secondary downstream effects as many of these occur close to the point of damage.
For a start Epigenetic changes are very much part of the telomere - P53 - PCG axis which is linked to mitochondrial function and metabolism. What is the SENS proposal to address the underlying damage behind this? eg, ROS and other damage, DNA damage, P53 dysregulation etc... The underlying causes of this dysfunction are somewhat varied so what will SENS do about telomere dysfunction to stop that cascading the entire system? or should we focus instead on things that address that dysfunction eg, balance the PCG1 level to it induces TERT and regulates P53 correctly and helps prevent critically short telomeres, reduces oxidative damage and mitochondrial dysfunction? How does SENS propose to repair this.
Don't get me wrong I broadly support the SENS approach for clearing out junk etc... but I do wonder about this sort of thing and how SENS proposes to deal with issues such as the above. Not messing about with metabolism per se but addressing fundamental cellular mechanics such as telomere dysfunction and the resulting dysregulation of cells.
RepleniSENS would help address cell loss and ApoptoSENS to remove the zombies but even so how about addressing the underlying damage as Reason often talks about?
Replacing the lost stem cells is not going to work as the aged system resists them and taints the cells as the Conboys demonstrate. Yes the niche can be signaled to be more youthful to accept the new cells but that is messing about with metabolism.
Struggling to see how such problems can be addressed totally by SENS strategy. Sure we need to repair the damage but I dont see how the above posted issues are addressed.
Steve, the presence of the poor signaling environment is caused by malfunctioning cells (which cause a worse environment, which causes...) Changing the chemical balance to allow stem cell growth isn't "messing with metabolism" in the sense that Reason usually means. The Conboy lab is working on exactly what you're talking about.
Sorry, didn't phrase that right. A poor signaling environment causes systemic damage, which causes more malfunctioning cells, which cause a worse signaling environment...
Lower in the comments section has something from Dr. Conboy talking about this.
@SteveH: first, that's a bit of a non sequitur: loss of cells (both somatic and stem/progenitor) and accumulation of senescent cells are themselves key forms of the cellular and molecular damage of aging. They both contribute to the dysregulated signaling environment: senescent cells via the inflammatory factors and mitogens from the senescence-associated secretory phenotype (SASP), and cell loss acutely because of necrotic processes and long-term because of loss of binding, crosstalk, and direct interactions between the stem/progenitor cell and its niche. Ablating the former and replacing the latter are key forms of repair of the damage of aging, which will contribute to the normalization of the overall aging signaling environment.
Other examples include cells harboring mitochondria with deletion mutations in their genomes, which increase oxidative stress systemically (repair strategy: allotopic expression); foam cells in local atherosclerotic arteries, which generate inflammatory and other deranged signaling (repair strategy: novel hydrolases to clear the foam cell lysosome and rehabilitate the macrophage); other intracellular and extracellular aggregates, including (in the muscle tissue) differentiated muscle cells with intracellular β-amyloid accumulation (which is characteristic of aging muscle and linked to sporadic inclusion body myositis (sIBM) (strategies: novel hydrolases for the former; removal, such as by immunotherapy, for the latter); the systemic effects of accumulation of excessive visceral adipose tissue macrophages (strategy: ablation); adipocyte replacement or transdifferentiation in aging muscle (ablation and replacement with stem cells); etc. Damaged cells and macromolecules lead to compensatory or dysfunctional changes in the signaling environment; repair the damage, and the signaling environment is to that extent normalized. Comprehensive damage repair will by definition lead to a structurally young body, which will result in a comprehensive reset toward a youthful signaling environment.
@Michael: Good answer! Thank you.
Regards foam cell removal there are a number of papers around suggesting that restoration of gene expression help clear such cells. Therefore would it not be a good idea to focus on stabilizing the network first then seeing what else needs fixing? In other words support work by the Conboys (perhaps support their work on lifespan.io) that directly stabilizes the network then see what is left. I know the Conboys and they are hoping to launch 2-3 new projects to make rapid progress, can we not all work together on this to get it done?
@Michael Would it possibly be a viable approach to clear the niche of resident Stem Cells which resist engraftment of new implanted MSCs so that the new cells simply replace them rather than trying to fight the dysfunctional system?