Short notes: massively parallel in vivo screening; thoughts on senescence and telomeres

Recently, I attended two very useful seminars/talks. There are two kinds of talks. Those seminars that are helpful, but boring. And those that leave you amazed at every step. The boring ones can be useful when they give your mind time to wander, and ponder some minor detail of the talk, or think about your own research. These talks had a little of both worlds:

1. FunSel: Functional in vivo selection using adeno associated viruses [AAV].
AAV lead to efficient infection of post-mitotic tissues. Selection is based on a simple principle: if AAVs express protective proteins, they will be enriched in surviving cells. The main assumption is that there is some selection on the cell level, e.g. some cells die, others survive. If this works, you could imagine applying it to most diseases e.g. neurodegeneration, beta-cell death, muscle cell loss (sarcopenia), etc.
I am still searching for publications on this topic, as it appears that most of the research is still ongoing.

How could we adapt this technique to aging research if it works as promised? For example:
A. Using FunSel with a model of mitochondrial aging (the interested reader can figure out which one I mean)
B. More speculative: Using it for in vivo optimization of amino acid sequence and function, e.g. vector optimization

2. A seminar about telomerase, senescence:
Telomere attrition may be a feature of dividing cells in particular, e.g. endothelial cells responsible for angiogenesis. This can be seen microscopically in a vessel section where only some cells show critically shortened telomers, presumably, descendants of a dividing cell that formed this (part of the) vessel. I am now slightly more inclined to consider telomere length when it comes to the natural human lifespan.

Importantly, telomere attrition may lead to senescence and the senescence-associated secretory phenotype (SASP) is generally considered to be detrimental. However, the senescence-associated secretory phenotype (SASP) might have some protective effects as well. For instance, selected proteases in the skin may damage elastin, collagen and basement membranes, but they can also clear the way for immune cells to access and destroy senescent cells.

Thus it might be best not to mess with the downstream effect of aging - here: SASP - but to target the events that are upstream. Alas, we do not really know what these are.

I'd like to emphasize that the elegant method of senescent cell ablation circumvents this problem (2a, reviewed in 2b. Note: this is in a progeroid model); removing senescent cells before they can cause damage does not require us to understand how these cells arose in the first place. Eagerly, I await data from healthy aging rodents.

1. "Generation of AAV-based, arrayed genetic libraries for in vivo functional selection: an innovative approach to identify secreted factors and microRNAs against degenerative disorders"

Nature. 2011 Nov 2;479(7372):232-6. doi: 10.1038/nature10600.Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Baker DJ1, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM.

2.b. Nature. 2014 May 22;509(7501):439-46. doi: 10.1038/nature13193. The role of senescent cells in ageing. van Deursen JM.