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.
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.
(a) created a protein interaction network of longevity-related genes using human homologues of yeast/worm/fly known to increase longevity (b) compared the genes encoding these "longevity network proteins" to genes change in expression during human muscle aging (c) 6 of 18 homologs of 18 human FRAP1-interacting proteins that differ between young and old muscles extended worm life-span
So we have (1) evidence that there is good shared gene networks between worm and human, so it's a good model and (2) a list of interesting additional candidate longevity genes
The authors put it better; "we show that human homologs of invertebrate longevity genes change in their expression levels during aging in human tissue" and "These observations taken together indicate that the broad patterns underlying genetic control of life span in invertebrates is highly relevant to human aging and longevity. We also present a collection of novel candidate genes and proteins that may influence human life span."
It makes sense that we should share the same basic longevity repetoire with worm, given that the aging process affects most of life.
They focused mainly on FRAP1 then, with strong evidence that FRAP1 homologues are important for longevity in other species.
They tested 18 homologs of FRAP1 interacting genes in yeast (basically they fed worms with bacteria expressing double stranded RNA corresponding to genes encoding the different FRAP1 interacting proteins). Generally, extension of lifespan was obtained (Fig 6). This quote discusses the most interesting candidate:
"Knock-down of rps-27 expression in nematode resulted in 50% and 44% increases in life span in two independent experiments. Mammalian RPS27 encodes a zinc finger-containing protein component of the 40S ribosomal subunit . Several studies have established that TOR signaling can modulate life span in yeast [30,32] and fly . It has been demonstrated further that inhibition of translation can also extend life span indicating that loss-of-function in TOR signaling modulates aging through an effect on rates of translation [41–43]. Since RPS27 is a component of the ribosome and interacts with FRAP1 (Tor), it is likely that the life span extension seen in the rps-27 knock-down is due to an effect on rates of translation either through TOR signaling, direct effects on ribosome structure, or a combination of the two."
Interesting! I wonder what the "side effects" of inhibiting rates of translation might be? From GeneCards, the gene is implicated in various cancers. Generally, the gene doesn't scream out:
"Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S27E family of ribosomal proteins. It contains a C4-type zinc finger domain that can bind to zinc. The encoded protein has been shown to be able to bind to nucleic acid. It is located in the cytoplasm as a ribosomal component, but it has also been detected in the nucleus. Studies in rat indicate that ribosomal protein S27 is located near ribosomal protein S18 in the 40S subunit and is covalently linked to translation initiation factor eIF3. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome."
More investigation needed, for instance perhaps the entire S27E family of proteins are integral to the aging process? Anyway, sticking to RPS27 or MPS-1, Metallopanstimulin-1, the gene that encodes the protein it seems to reduce the growth of tumours, see this article. So, the gene could protect against cancer formation. How this relates to an increase in life span when the gene is knocked down in worm is not readily clear. In human, might knocking it down increase the risk of tumours?
Ok so here we go. I'm a post-doctoral researcher (bioinformatics), working mainly in neuropsychiatric genetics. Getting interested in genetics of aging, so going to used this blog to archive ideas/research/interesting papers.
Resveratrol has interested me for a while now....Ron Evans Salk institute: "marathon mouse"....AICAR drug...AMPK and PPARdelta agonists are exercise mimetics. - CELL '08 PMID: 18674809 ...Roger Felding - Tufts
http://www.bodyofwealth.com/entry/aicar-drug-may-cure-obesity/ - AICAR to cure obesity "exercies in a pill"