Antagonistic Pleiotrophy, Catabolism, Rapamycin

[Deborah_Hall]

Would welcome inputs to the following train of thought and questions: Is there an inherently more “catabolic” genetic predisposition? And if so, would this impact the relative value of rapamycin?

As we know, the concept of antagonistic pleiotrophy now informs much of what we understand about aging: certain genetic predispositions or traits that are beneficial in youth, and for reproduction, can be harmful in later life.

Can it be that we all have a genetic predisposition to be on one side or the other of the growth/high reproduction/anabolic side (versus the lower growth/less successful reproduction / catabolic side?

I have read some evidence, eg. very long lived people tend to be smaller in stature (and what about those Laron dwarves!). And I believe Nir Barzilai has found that among centenarians there is a genetic “flaw” that reduces the cell’s ability to take up IGF. Even with normal IGF in the blood, it doesn’t get into the cell. Do some long lived people have a more “catabolic” genetic makeup?

Do I myself? Women in my maternal line (and myself included) tend to be short and small boned (with lots of osteoporosis, a catabolic process). After having one child at age 34 I had two misses and then very early menopause – reduced fecundity. My grandmother, aunt and mother all lived into late 90’s or over 100 (with Alzheimers, but that’s another story. Anyway, it seems that if you get past 90, there is about a 75% chance you will have some neurodegeneration).

While my health is quite good, though not perfect, I am aging well thus far. (I do work at it).

I am wondering whether I am more inherently “catabolic” and if Rapamycin is going to be as beneficial for someone like myself, say, compared to more “high growth” innate disposition.

Are we all inherently more or less anabolic or catabolic?

And if so, should that effect our priority of worries and our strategies?
(Take rapamycin versus make sure you get a lot of protein? value of calorie restriction for longevity purposes if you are inherently “catabolic.”?)

I don’t mean to propose this as a theory of everything: of course there are other dimensions such as cardiovacular health, lipids, possible predispositions to atherosclerosis, diabetes, that are all overlays to this.

[Herm]

You raise some really good questions, the answer is 42. Seriously, I think a lot more work will need to be done to better understand the underlying mechanisms of mTOR regulation, which in turn may provide pathways to answer your interesting conjectures. One way to approach it is to ask if there are phenotypes associated with higher or lower mTOR activity and regulation, and if there are genetic differences that may in part explain the phenotypes. The complexity of mTOR regulation, can be seen here in this Nature report. That first image, outlining what is known about upstream and downstream mTOR related genes involved in mTOR activity shows the complexity of mTOR regulation. In this case, mutations in RHEB which is upstream of mTOR do result in phenotypic differences in brain development. I suspect in the future, additional examples will be found. Given the complexity, I suspect that the resulting phenotypes would result in a spectrum of catabolic <------> anabolic phenotypes, relevant to this discussion.