Comment on CR mimetic drugs and nutraceuticals potential

From what I understand, iirc, CR works even outside the parameters that can ever be found in nature.   That is IIRC, even up to 65% restriction resulted in 65% increase in lifespan in mice.   It is extremely unlikely, virtually impossible, that on 65% restriction on a famine you will find extraordinarily micronutrient fortified food with minimal effort(as large effort will also result in death from excessive calorie burning from activity) as provided in the lab.
   
I've also heard that on CR started on adult organisms, the transition into CR needs to be gradual and not sudden to actually confer benefits.   The food also has to be fortified to provide sufficient micronutrients.   Again it would seem to be that famines might occur quite sudden and drastic, and may reduce micronutrient availability.

Even in the lab it may be that the mechanism could even go further if not for the low calories compromising vital functions.    On higher lifeforms like man the minimal calories necessary to not jeopardize function may be even higher(I've heard of some severe calorie restriction individuals losing bone integrity), but the genetic expression flexibility may still remain.

What will tell the true limits of these pathways are the physical limits in terms of gene expression that they can ever reach with interventions such as drugs or nutraceuticals.  Which may be reached at 65% CR or could be higher had it been physically possible to survive on even less calories.   CR mimetics stimulate the pathways without jeopardizing function from insufficient calories.

We now know that things like NAD+ drop with age in some organisms which may be behind why resveratrol failed on healthy organism with longer lifespans of a few years after succeeding in many organisms of lower lifespans such as yeast, c. elegans, fruit flies, and some short lived fishes.   Sirtuin dependence on NAD+ would obviously be compromised if NAD+ levels fall too low.Since resveratrol works in part through sirtuins it's effects would be adversely affected through such age associated changes.  But ways to increase NAD+ are now known, some readily available some on the horizon.

source Josh Mitteldorf scienceblog comment

Short term extreme CR leads to extreme weight loss and appears to cure type 2 diabetes in small group of patients

 Desperate for information, I headed to the web, where I found a reportabout a research trial at Newcastle University led by Professor Roy Taylor. His research suggested type 2 diabetes could be reversed by following a daily 800-calorie diet for eight weeks....

Others have also changed their lives through the diet. Carlos Cervantes, 53 and from the US, was at death's door when he tried it. He weighed 120kg, suffered a heart attack in spring 2011, his eyesight and kidneys were failing and he faced having an infected toe amputated. He even had fungus growing out of his ears, feeding on his ultra-high blood sugar levels. But after seeing a TV report on the Newcastle research, he started eating only 600 calories a day, replacing the supplements with not just vegetables but fruit, lean chicken, turkey, occasional bread and a daily milkshake. Two months later he had lost 40kg and 18 months later he is still free of his type  2 diabetes...-link1

The small study, which was followed independently by people in the above article, will be looked into with a bigger study involving 100s of patients as seen in the following quote.   Of course extreme CR probably requires medical supervision and should only be used short term to avoid side effects.

 Overweight patients who were put on a diet of just 800 calories a day were free of the disease within a few weeks of following the strict regime....

The diet, which was tested on 11 patients, is a key part of a new £2.4million medical trial of almost 300 people with obesity-induced diabetes....

In healthy people, the liver should contain around two per cent of fat, but in obese people, it can reach 40 per cent and suppress insulin production. Professor Taylor said the results were “enormously exciting”.

He added: “The good news is that if you cut fat in the diet then the liver fat falls very rapidly and that means the pancreas can start working again.”

The new study will see 280 patients with Type 2 diabetes monitored for several years – with half of them on a crash diet for eight to 20 weeks.

Professor Lean said: “We’re confident that some people with Type 2 will be able to achieve remission.-link2