Excellent set of slides

[ApropoE4]

http://www.ucsfcme.com/2015/MNR15001/sl ... orders.pdf

[LillyBritches]

Those certainly are some awesome slides. I love this:

Essentially, all models are wrong, but some are useful.
George Box

Yep. Also, Dr. Mahley...I wrote him 'bout two years ago whilst I was still freaking out about my status. I mean, real Lady Macbeth, center-stage, hand-wringing stuff. He responded with one of the lengthiest, most informative, kindest, and reassuring emails I've ever received from a brilliant scientist. Upon scrolling, I recognized Dr. Dubai, and realized that she's the researcher who is getting the word out re the Klotho KL-VS variant. Nice.

Obviously, I'm hoping this variant will prove highly protective...because I have it. Dr. Dubai's study:

In the current study, the researchers found that people who had 1 copy of the KL-VS variant performed better on a battery of cognitive tests than those who did not have it, regardless of age, sex, or the presence of the APOE ε4 allele, the main genetic risk factor for Alzheimer's disease.

http://www.medscape.com/viewarticle/824997

My mom has the variant, too. She's 3/4. If she's any indication (albeit anecdotal, of course): She's 94 1/2 now and was cognitively fabulous until she reached around 89-90. She's not really progressed with whatever she has.

Thanks much for posting this!

[circular]

Lilly how did you find out your Klotho KL-VS variant? I don't see it in Promethease?

[circular]

Hmmm, looks good. Wish I could have listened to the talk and I might take in more One thing that stands out, if I skimmed it right, is that suppressing inflammation may undesirably suppress beneficial neuromodulation being performed by the immune system, and modifying immune function may have different effects (beneficial and not) at different stages. Now that is humbling on top of all the other complexities!

[ApropoE4]

I think they're trying to make a compelling case for their small molecule development.

If I read the numbers on their APOE4 structure corrector patent right, it's not sufficiently effective on its own (and will probably be even less so in humans), but perhaps a combination approach of that, Klotho uppers, Ab clearance agents, etc. might do the trick (and can be marketed as effective for more than just the 4/4 niche). Note that exercise is the only lifestyle factor they seem to be (speculatively) hopeful about.

[pgf54]

Circ I think Lily is referring to RS9536314, however please correct me if I am wrong...I am heterozygous Gt which I believe is the positive one to have. Its the G allele that gives benefit?

[Teezer]

There seem to be two SNPs involved: rs9536314 and rs9527025.

I'm homozygous on the first one. The second one is not listed in my 23andme dump. I'm guessing that that means I'm not a carrier of the KLOTHO variant.

[LillyBritches]

Circ I think Lily is referring to RS9536314, however please correct me if I am wrong...I am heterozygous Gt which I believe is the positive one to have. Its the G allele that gives benefit?

If you're GT, pgf, you have the variant. But, no. It's not the "G" allele, per se, that's beneficial. In fact, if you're GG on this SNP, it's harmful. TT is common and I think it's neutral.

The only good allele to have on this one is GT. That's the KL-VS variant.

Teezer said:

There seem to be two SNPs involved: rs9536314 and rs9527025.

I'm homozygous on the first one. The second one is not listed in my 23andme dump. I'm guessing that that means I'm not a carrier of the KLOTHO variant.

Yes, Teezer, those are the SNPs that compromise the KLOTHO variant. However, they're in linkage disequilibrium, and rs9536314 calls the variant. If you're GT on that one, like pgf and I are, you have the beneficial variant.

A common variant of the human KLOTHO gene (KL), is reproducibly associated with longevity [4,5]. The Klotho protein is encoded by a 50-kb gene on chromosome 13q12, which consists of 5 exons [6]. A haplotype, "KL-VS", composed of six single nucleotide polymorphisms (SNPs), spans exon 2 and its flanking sequence and is present in approximately 15% of Caucasians [4]. Two of these SNPs result in amino acid substitutions: F352V (rs9536314) and C370S (rs9527025). "KL-VS" refers to the V and S alleles of these SNPs respectively, and since all six SNPs occur in perfect linkage disequilibrium, a single variant, F352V, can be used to tag the haplotype [4].

http://www.biomedcentral.com/1471-2350/7/51

http://www.snpedia.com/index.php/Rs9536314