Population genetics of aging

So today I was going to just look at mTOR in its own right, encoded by the FRAP1 gene. Wikipedia has a page on it - quite detailed - so I won't reinvent the describtive wheel. There's also a nice, though date, review here (pdf). It is probably at the heart of all this but instead the population genetics of aging is an interesting area to look at.

Population genetics?
Someone must have looked at SNP allele frequencies in long lived vs. short lived people or something...? Lo' and behold, a pubmed search of "FRAP1 aging" gives a paper called "Genetic variation in healthy oldest-old", published in PLOS. Great!

Small sample size, but it's a start: 47 > 85-year olds, followed by deep re-sequencing across functionally important regions of 24 candidate genes, as they write, genes implicated in "dietary restriction (PPARG, PPARGC1A, SIRT1, SIRT3, UCP2, UCP3), metabolism (IGF1R, APOB, SCD), autophagy (BECN1, FRAP1), stem cell activation (NOTCH1, DLL1), tumor suppression (TP53, CDKN2A, ING1), DNA methylation (TRDMT1, DNMT3A, DNMT3B) Progeria syndromes (LMNA, ZMPSTE24, KL) and stress response (CRYAB, HSPB2)".
You can see FRAP1 in there, the gene coding for mTOR.

So it seems they have catalogued a fair number of variations across these genes - 848 single nucleotide polymorphisms and 87 insertion/deletion polymorphisms. It's a good start. As they say "As a first step towards investigating the effects of genetic variation in aging-related genes on human lifespan and health, we characterized genetic variation in healthy oldest-old."

Clearly, a number of these variations are likely to have an affect on aging. Perhaps they are protective, or alternativly their absence migh increase susceptibility.

An interesting note is that they also look at HapMap. HapMap (see website) is a widely used reference panel of human genomic variation. What the authors say is that "only 12% of variants (179/1550) are shared between available HapMap SNPs and sequencing data generated from our healthy oldest-old". They don't comment on why. One reason could be that these variants are specific to their "healthy old" population, which are probably therefore a unique population, i.e. in a typical population not nearly as many people would live to be as healthy and as old.

The interactions between SNPs would also be very cool to look at - what combinations of SNPs might increase risk? (a) more samples are needed, (b) a matched "control" (old but with diseases) might also be relevant.

But it's a good start!

Rapamycin, Resveratrol and longevity

Some interesting studies of rapamycin and resveratrol have emerged. Once study finds that it can slow down cellular senencence at high concentrations. Apparently, resveratrol also does. At this point many studies have shown resveratrol to (a) delay aging and (b) slow down the onset of age-related diseases (obviously not mutually exclusive events). Resveratrol activates sirtuins but it has other effects also, not all completely known. For a cell, and by extension a body, to age, you need (a) cell cycle arrest and (b) an active mTOR pathway. Basically mTOR causes aging by making cells proliferate more, and resveratrol can inhibit this via a mechanism of S6 phosphorylation.

Rapamycin can inhibit the mTOR pathway (see this study, the last line of the abstract of which I love - "Our data demonstrate that senescence can be pharmacologically suppressed."!). In addition, it prevents the loss of proliferative potential associated with cellular aging.

A conclusion of the above study was that resveratrol can be toxic, so it's a trade off between toxicity and anti-aging effects. Lower level can be quite effective however, the authors state, e.g. 2-3 fold preservation of proliferative potential (as opposed to 10-fold). Even transient inhibition of mTOR might be enough to have some effect on cellular senencence.

Various discussion about the exact interplay between mTOR, sirtuins, resveratrol etc. are then discussed. A bit over my head!
(a) sirtuins + mTOR = same pathway. Thus, activate one, inhibit the other...(evidence, e.g. that resveratrol inhibits PI3K, an upstream activator of mTOR)
(b) resveratrol, like anti-diabetic drug metaformin activated AMP-activated protein kinase which activates mTOR

So, one way or another resvertrol targets mTOR and the key is to use it at non-toxic doses. Up to 5g is apparently not toxic to humans - see this and this study.

Another study shown resveratrol increasing AMPK activity in mice (i.e. inhibiting mTOR).

The final conclusion if that rapamycin and resveratrol could work very well in tandem and at non-toxic doses to delay aging. Interestingly, here's the company of the authors.

See also this link and this link for some more info/discussion.