The further a society drifts from the truth, the more it will hate those who speak it. ... In a time of deceit, telling the truth is a revolutionary act. George Orwell

Saturday, September 19, 2015

Longevity genes, glucose and insulin sensitivity

Some of the most interesting longevity research concerns FOXO3A (homozygotic GG) and SIRT6 genes. In the case of FOXO3A, it seem to be associated also with the improved insulin sensitivity (thus allowing the body to maintain consistently LOW insulin level, reducing the risk of insulin resistance, metabolic factor and diabetes t2) throughout one's life. In the case of SIRT6 which plays a major role in DNA repair process, it appears to be upregulated with lower glucose consumption. Insulin and carbohydrates, carbohydrates and insulin...

Lots of unanswered questions: is the link accidental or not? Which is the primary and which is the secondary factor in the longevity?
Is (a) FOXO3A the primary cause of longevity while in addition improving also the insulin sensitivity? - Or, (b) is the improved insulin sensitivity and low glucose caused by the gene (or by whatever other factors...) - the primary longevity factor?

So far, the second answer (b) seems to be already demonstrated for the SIRT6 while there seems to be a growing suspicion that it is may be so for the FOXO3A as well!

This situation reminds me that the life forms may deals with any adverse environmental threat in the two-fold fashion: - either evolving a special resistance against a threat or simply avoiding the threat (in this case by not consuming the excessive carbohydrates...)

So, you either may already have the protective genes and in this case you can safely consume whatever high carbohydrate food is being marketed your way, or you minimize or avoid that stuff altogether. Everybody has a choice - and that's excellent news!

More links:

Bradley Willcox et al., "FOXO3A genotype is strongly associated with human longevity", PNAS, September 16, 2008, vol. 105 no. 37


Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/IGF-1 signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity.
Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype.

I also posted on this subject in post. See the following quote from this article about the SIRT6 gene:


One explanation for this failure may relate to SIRT6’s critical role in DNA repair. Several studies have indicated that SIRT6 helps catalyze repair of the damage at numerous types of DNA lesions, including single- and double-strand breaks. A characteristic feature of aging cells is an increase in the amount of DNA damage.
While overexpression of SIRT6 may not be tractable in a therapeutic context, SIRT6 activity can be increased by caloric restriction, reducing glucose consumption, or increasing NAD+ bioavailability (**) - interventions that have already shown promise in increasing longevity in animal models. (Such interventions are also showing promise in slowing the progress of some age-related neurodegenerative disorders.


Sam said...

On the left side bar the link to,

is really interesting. It's the same question I asked about how some people do well on ultra high carb diets a while ago.

Just a thought. The people on the rice, juice, sugar diet lost a lot of weight. People with stapled stomachs go on a starvation diet after the surgery and many were found to be cured of diabetes. A Doctor came up with the theory that their pancreas(I think) was clogged up with fat and the starvation diet unclogged them.

Maybe starvation is the key. With a lot of carbs it's tough to get enough calories and the pancreas is unclogged. With a high fat diet you don't get as many insulin stimulating foods so the end result is the same. Closely modulated insulin?

Maybe just starving yourself for three days a month would do the same and you could eat what you wanted.

I know this is rambling a bit but it is confusing.

Stan (Heretic) said...

I had similar thoughts some time ago when I started looking into nutrition and metabolism. I have been discussing a lot of those issues around 2000-2003 on webmd and other forums, mostly with vegans and diabetics. The pattern that I noticed (my subjective observations, not a science) is as follows:

1) overweight or normal weight people do initially very well on a low to medium caloric vegetarian low fat diet, based on natural produce (root vegetables, green vegetables, fruit and nuts in this order) but tend not to do well if they over-consume baked goods, commercial packaged food of any kind and/or lots of bread. However, eventually after a variable length of time depending on an individual body resilience, they begin experiencing some health deterioration due to common deficiencies (omega-3 DHA,EPA, vitamins A,B12,D3,K2, some aminoacids). The first organ that tends suffer are teeth, bone density, skin and joints. Then some neurological problems tend to show up, then thyroid and auto-immune diseases may flare up. It is highly variable and some small percentage of people may be able to tolerate vegetarianism longer than the other. I also noticed that lacto-ovo or pesco-vegetarians seem to do better than the strict 100% vegans, and especially better than 100% fruitarians. A strict fruitarian diet seems to cause neurological and/or mood disorder problems and is for that reason dangerous and actually banned by doctors in some countries for young children.

2) Diabetic t2 overweight people do well on such diet as above, but - if and only if they possess an iron will to stick to it! Note that for a diabetic person it is extremely difficult to tolerate low caloric diet of any kind low fat or high fat alike, because their metabolism is deranged on the cellullar level. Their cells do not assimilate glucose quickly enough except at elevated blood glucose concentrations and at very high insulin levels, and at the same time their liver is unable to manufacture enough of the alternative fuel - ketone bodies because of a too high insulin level. Thus, they generally crave and need the extra calories to overcome that factor and often feel ravenously hungry ("toxic hunger" symptom), more so that healthy people if deprived of food. If they suddenly indulge in food then all the benefits of a vegetarian low fat diet disappear and their diabetes or diabetic symptoms and the diabetic risks involved (cardiovascular!) may come back. Note - the risk factor does not always manifest itself by the high glucose but also as high insulin and in terms of other hormonal anomalies, for example thyroid.

3) Underweight people of any age and any health status generally do very poorly on vegetarian low fat diets, especially after a couple of years. That was I believe the case with Denise M. She seemed to have became run-down after a few years and had to stop. I could not do a vegetarian diet in my 30-ties either for the same reason! She is most likely of "Vata" body type (I am too) and people like us simply have to consume a high caloric density (but low absolute caloric intake!) nutrition! The healthiest form of high density foodstuff is animal fat. That's what I eat - animal fat, vegetables and meat, in this order. The least healthy form of high density food for us (Vata) is sugar and concentrated starch products because of the insulin spikes. We don't have a good tolerance against that!


Sam said...

I was reading about the potato diet the other day and had a brain flash/fart. Maybe the whole thing is about gut bacteria. Apparently an all starch diet with lots of resistant starch leads to a proliferation of a type of gut bacteria that's very good for you.

I think I even remember it being said that this gut bacteria helped produce some of the same changes that intermittent fasting produced.

My Dad said the only diet that ever really worked for him and made him feel good at the same time was the rice diet. Very boring though.

I wish I could find the potato diet link. I thought I saved it but I can't find it.

Sam said...

Found the potato diet link,

"...the paper, “Butyrate and Propionate Protect against Diet-Induced Obesity and Regulate Gut Hormones via Free Fatty Acid Receptor 3-Independent Mechanisms”6. This study, which should win an award for ‘Most Boring Title Ever’, describes in excruciating detail the exact mechanisms behind a huge burst of short chain fatty acids (such as butyrate and propionate) as seen in the Potato Diet, this study concludes:

“In summary, the present findings demonstrate butyrate and propionate [a gut-bug created fat] regulate gut hormone release, suppress food intake, and protect against diet-induced obesity. We also show that FFAR3 [a hunger hormone] is required for maximal GLP-1 [another hunger hormone] induction by butyrate, but is dispensable for butyrate- and propionate-dependent effects on body weight and GIP [another hunger hormone] stimulation. As enteroendocrine [hormone producing] nutrient-sensing and the incretin axis [insulin sensitivity] are subjects of intense interest in drug discovery for metabolic disorders, future studies to determine the signaling mechanisms responsible for SCFAs' beneficial effects may have a major impact on the development of novel therapies for diabetes and obesity.”

TRANSLATION: Find a way to make your gut bugs produce fat and you will be healthy, lean and not hungry, ie. the Potato Diet

Stan Bleszynski said...

Hi Sam,

Interesting study. That's probably why, as far as high vegetable high carbohydrate diets go, those based on potatoes or rice are relatively much less unhealthy than the grains or sugar loaded diets.

The problem with wheat based diets as opposed to potatoes or rice, is probably caused by the wheat itself somehow derailing the necessary conversion due to its specific mix of phytotoxins.

It also reminded me of an article that pointed out that over 2/3 of calories assimilated by cattle like cows, goats and sheep are from butyrate and similar short chain fatty acids synthesized in their gut by microbes. It is kind of paradoxical to find out that the cattle while eating moslty grass thrive in fact on the "high fat" diet! 8-:)