CR4 - Steven Austed:
How ubiquitous is the CR effect?

Reducing major cause of death in mice – cancer.
P53 mutant mice – reduced cancer rate but shorter life overall (!)

Two big questions:

• Has it really “worked” (almost) every time it has been tried?
• Irrespective of if it worked, are there any potentially deleterious side effects?

CR in invertebrates: yeast.

• reduction of 75%, 95%, 99.5% all increased lifespan.
• Different strain of yeast – same reductions incrementally reduced lifespan (opposite of first example)

• fed on sugar/yeast, CR induced by diluting the nutrients
• they usually do not know if the flies eat differently in the absolute, unfortunately (except that females eat more than males in the presence of more food)
• found that 2% yeast is the best amount – less/more they live not as long
• “chico” mutation extends life in females, but it has nothing to say about CR – in some feeding situations chico can shorten life span

• 7 of 10 species studied lived longer on CR, 3 were shorter.

• only good study that knows with certainty the actual food consumption

CR in vertebrates: guppies.

• wild guppies, not domesticated
• 2 of 4 groups of guppies had shorter lives on CR (they were “high” predation environment); the other groups lived longer (low predation groups).

• Labrador retrievers; fed 75% of ad lib, began at 8 weeks and ended at 3.25 years – they then switched all to low protein diet so they would reverse the obesity trend.
• Restricted lived 12 years, other group lived 10.8 years. Statistically significant.
• Unfortunately, most of the dogs were euthanized for arthritis (according to humane standards), so they did not live natural life spans.
• However, CR dogs were euthanized at later ages at a rate that might still be statistically significant.

• B10 mice
• Many inbred mouse strains were tested, and sorted for gender. Average extension was between 21-56%, depending on the diet and individual

• Similar to mice, increases from 12-30%

CR studies – things to consider: environment (food, water, temp, germs) and genotype (sex, etc.)

Shortened life span in a particular study of Snell Dwarf mice – but these are same mice used in current studies to demonstrate CR effects. Difference? The early short life study was not controlled for pathogens/infections.

Taking mice, stapling their intestines and poking a hole in it to induce an infection and then CR’ing them showed a deleterious effect versus ad lib fed mice.

CR’ed mice survive better when injected with paraquat.

CR’ed mice who were aged and inoculated with influenza did NOT survive as long.

[MR comments that there is another study showing much longer increase in life span which might be due to TH1 response (anti-inflammatory effect), but this study is not often cited for unknown reasons.]

[Mary comments that we might want to stop CR in the situation of the impending bird flu pandemic, as we could be more susceptible to it with less bodily reserves (?)]

Levels of adiposity vs CR: getting hugely overweight mice to go from 67% to 48% bodyfat by CR makes them live just as long as mice that went from 22% to 13% via CR. Wow.

WILD MICE: 40% restricted, increased stress hormones: it did not increase the mean life span, but the very longest lived in the group were all CR’ed. Interpretations? There is genetic variation that could cause CR effects to vary widely among individuals? Or – it just doesn’t always “work”, period.