Donnerstag, 20. Juli 2017

Aging across the tree of life?

Just read a beautiful paper and I am not disagreeing. Just criticizing their approach and conclusions to learn something for myself. So let's see. Aging is conserved in different species, right? The authors (2, 3) claim that there are big problems with this assumption and I will discuss the two articles together.

Here we contrast standardized patterns over age for 11 mammals, 12 other vertebrates, 10 invertebrates, 12 vascular plants and a green alga..Although it has been predicted that evolution should inevitably lead to increasing mortality and declining fertility with age after maturity, there is great variation among these species

 Furthermore:
More sophisticated analyses including both shape and pace have confirmed the importance of slow, negligible, and negative aging [44].One of the most striking findings in recent years is that demographic aging appears to be far from universal [3,39]
......
This finding is crucial and paradigm-shifting because it implies that there is no single, universal aging pathway. At most, there might be a pathway that is shared when aging is present but can be turned off. 

Freitag, 7. Juli 2017

Current issues in GH/IGF1 research: adult-onset studies and mediators

CR, calorie restriction
IGF, insulin-like growth factor
GH, growth hormone
GHRKO, growth hormone receptor knock out
MLS, LS, (maximum) lifespan

In this post I would like to expound on an idea that allows us to make sense of the studies on adult-onset GH/IGF1 deficiency. As a disclaimer, let me emphasize that I am not working in this field, but I do try to keep up with the literature.

The search for independent pathways: why study these animals at all?
One unresolved question is linked with the evolvability and mutability of lifespans. Given that LS is quite flexible within and between species, we would expect the existence of lifespan assurance mechanisms, and most likely they should include signalling pathways and transcription networks, because these can change quickly over reasonable time frames. This is the optimistic view that many biogerontologists agree with. In contrast, the pessimistic view holds that CR-related pathways are a curiosity and normally changes in lifespan require thousands of independent mutations in wildly different pathways, precluding significant human lifespan extension using drugs or other interventions.

So far we know that there exist partly redundant longevity-assurance pathways that are all loosely linked to CR, anabolism and perhaps cellular "quality control" and multistress resistance. It will be very important to define the degree of overlap between these pathways to clarify whether the optimistic or pessimistic view is closer to reality. We need to know if there are pathways that are truly distinct from CR or that produce additive benefits with CR even if they are redundant.

In the end, we need to know how to combine interventions to achieve the best results, i.e. which genes are epistatic and hence in the same signalling cascade. We have to answer questions such as: How much of the effect of CR is due to GH and IGF1? Is protein and methionine restriction operating through the same mechanisms as CR? It seems, both of these overlap with CR but are distinct. What about mTOR? It seems linked to GH, IGF1 and CR but distinct (long-lived GH dwarfs have diminished mTOR signalling for example but mTOR inihibtion produces a different phenotype from dwarfism). What about the two novel players, c-myc and H2S?