Re: Calorie Restriction: Does it work as well as mice as on humans?

February 15, 2006

Hi :

Gosh . That is an interesting article thank you. Three parts I

found particularly notable were:

1. On dissociating leanness from caloric intake:

" About five years ago [Kahn] started breeding mice in which he had

genetically knocked out insulin signaling from one tissue at a time:

muscle, in the MIRKO (muscle insulin receptor knockout) mouse; fat in

the FIRKO mouse; liver in the LIRKO mouse; and brain (neural tissue),

in the NIRKO mouse. " What struck us about the FIRKO mouse, " Kahn

says, " is that it remains lean as it ages, protected against obesity

even on a high-fat or high-calorie diet. " This provided an

opportunity to dissociate the two things that happen in caloric

restriction. For example, in CR, leanness is associated with

decreased food intake. " But in the FIRKO mouse we had an animal that

ate as much as a normal mouse and yet remained lean. In fact, it ate

even more than normal relative to its body weight. " He could then ask

the question, would being lean by itself promote longevity in a mouse

that was eating normally? " Sure enough, " says Kahn, " the animals

lived longer, by 18 to 20 percent. " The reason for their longevity

might be related to the leanness, but could also be related to the

disruption of insulin-signaling, Kahn allows, even though, in the

FIRKO mouse, insulin signaling has been disrupted in only one tissue

of the body. To Kahn, this suggests that in mammals, the links

between insulin signaling, caloric restriction, and obesity could be

centered on fat tissue. "

2. ON the thermodynamics issue:

" The FIRKO mouse eats a lot yet remains skinny, suggesting it has a

high metabolism. How is it burning all the extra calories? " We

haven't figured this out yet, " admits Kahn. " The obvious answer would

be that they are more active. " But they aren't: " If you put them in a

cage that has light beams that measure how much they move around,

FIRKO mice are not more active than normal mice. " Even their internal

body temperatures are the same. " Obviously, they must be burning off

the energy in some way, " continues Kahn, " because if you take in the

calories, you either have to store them, burn them, or excrete them.

They are not excreting them, so we believe they are being burned up

in excess energy utilization by some mechanism that does not involve

being more active. " One hypothesis is that the FIRKO mice are

metabolically inefficient. Kakn has observed that normal mice, like

humans, vary in how much weight they gain for a given amount of food

that they eat. " Some mice will literally gain 30 percent more weight

on the same amount of calories than another mouse, " he says. " Others

are just like friends who say that they can eat anything and never

gain weight " (though he notes that quantifying and correcting for

varying activity levels can be difficult). "

3. On resveratrol:

" Sinclair has begun feeding mice resveratrol, the best-known of his

sirtuin-activating compounds derived from plants, and reports that it

suppresses the growth of implanted cancer tumors. He is also feeding

it to healthy mice to see whether it increases their longevity. The

molecule " seems to be a very potent cancer-preventive agent, " he

reports, and is currently in clinical trials for colon cancer on the

one hand, and, because of its antiviral properties, for oral herpes

on the other. " It should also have benefits for diabetes, " he says,

and it has been shown to be effective in animals " against heart

disease, stroke, and high cholesterol. It looks like it is going to

become a super-aspirin in the future. "

Rodney.

>

> Here is an interesting extract from the following article:

> http://www.harvardmagazine.com/on-line/090548.html

>

> Demetrius's hypothesis (see " A New Theory on Longevity, " November-

> December 2004, page 17) links evolutionary history to longevity,

> arguing that organisms that mature late sexually, have fewer

> offspring, and spread their reproductive activity over a longer

> period will also be long-lived, because the metabolic stability of

> their cells and cellular networks have evolved to accommodate this

> life history. And because such animals already enjoy high levels of

> metabolic stability, interventions like CR (and, presumably,

> stability of cellular networks—will not benefit them as much as it

> will benefit species characterized by early sexual maturity, a

> narrow reproductive span, and large litter size: traits that

reflect

> a survival strategy of the sort that one finds in mice, which

> evolved to cope with feast-or-famine circumstances. " Darwinian

> fitness in a mouse is characterized by flexibility, " he

> explains, " the ability of a population to respond to unpredictable

> resource conditions, " whereas " Darwinian fitness in humans derives

> from being robust. The stability of cellular networks has evolved

in

> concert with population stability, " he says. And, in fact, human

> cells have been shown to be more resistant to stress than the cells

> of mice. His theory also explains why, in humans and other long-

> lived species, the rate of death ceases to increase exponentially

> after a certain age, which is not the case in mice. (Human

mortality

> decelerates after about age 85.)

>

> If Demetrius is right, then interventions that increase longevity

> will have large effects on the mean and maximum life span of mice.

> In rhesus monkeys, which share many genes with humans, he expects

> that results of a continuing caloric-restriction experiment will

> show a 15 percent increase in mean life span and have no effect on

> the maximum. In humans, he predicts the effect will be much less,

> adding perhaps 5 percent to average life span, and none to the

> maximum.

>

February 15, 2006