Speaker 12: Edward Masoro - Overview of Calorie Restriction and Aging

Long time and very respected CR researcher. Retired now.

Hasn't done research of his own in quite some time.

He likes the "new stuff" (like we've heard about today). But he has seen "new stuff" come and go :-).

McCay (1935) - First CR study to show longevity improvements when started soon after weaning. Hypothesized that it was a result of retardation of growth.

Later the growth retardation hypothesis was disproven by starting CR after growth completed. CR works independent of growth retardation.

Important topic - How late can you start CR and still get longevity improvements?

Lipman: two strains of rats. Started CR at 18 months (late middle age) and 24 months (old age).

She found no longevity improvements when CR started relatively late in life. Michael Rae suggested failure might be due to protein deficiency in her study.

But recent mice study showed late onset CR does work. Could be species difference.

Next question: Does CR slow intrinsic aging rate?

Max lifespan Definition: mean age at death of longest lived 10%

CR increases max lifespan, but max lifespan not necessarily a good marker of intrinsic aging rate.

Intrinsic Aging: Rate of decline in bodily systems. CR makes bodily systems seem more youthful, but is may not change slope (or rate) of decline.

NIA has found no good biomarkers of aging.

Different strains of rodents die from different causes - kidney disease, heart disease, leukemia. CR improves all of them.

But is preventing age associated diseases really an indicator of slower aging?

Mortality rate increases exponentially with age

Mortality Rate Doubling Time (MRDT): how many years does it take for mortality rate of a population to double?

MRDT in rats seems to go up when subjected to CR - suggesting true aging retardation.

But at young ages, CR in rats seem to DECREASE MRDT - young rats seem to "age" a bit faster. During bulk of adult life it

Michael Rae - in mouse there appears to be no effect of CR on MRDT.

Masoro suggest CR may DELAY the onset of aging in mice, rather than REDUCE aging rate as it appears to do in rats.

General observation: The only things that don't die are hypotheses of aging :-)

In other words, hypothesis of aging (and how CR works) never go away. Some people are always keeping them alive.

Example - CR works through growth retardation

Some people seem to see association between small size and longevity within some species.

But in ad lib fed rats, body weight not correlated w/ longevity, once food intake accounted for.

How about fat content?

Hypothesis: CR lengthens life through reducing body fat.

Masoro measured fat content vs. longevity in both AL and CR mice. No significant relationship.

Ob/ob mice live shorter ad lib. But after CR they still have lots of fat, but live as long as much leaner normal CRed mice.

Body fat is unquestionably bad in humans for longevity. Could be that fat is factor in humans but not in rodents. Could also be that fat isn't involved in aging, only disease.

Could be type of fat that counts for longevity - subcutaneous vs. visceral fat.

If you knock out insulin receptor in fat cells in rodents, they have less fat mass and live longer.

Masoro is critical of the several recent researchers suggesting body fat important for the mechanism of CR.

Next Hypothesis for how CR works: Reduction in metabolic rate

But in steady state CR, animals don't eat less per gram of body weight than ad lib fed animals.

Masoro actually found that lifetime food/calorie intake per gram of body weight (or gram of lean body mass) is HIGHER in CRed animals than AL animals (e.g. 133.5 vs. 91.5 calories/gram body weight).

But this was "food intake" measure, not metabolic rate.

So lots of people started investigating metabolic rate of CRed animals directly.

Metabolic rate (calories burned per gram lean body mass) doesn't go up w/ CR.

Should have been nail in coffin of metabolic rate hypothesis. But not so...

Reason people won't let hypothesis die is what you chose to normalize over - body weight? Lean body mass? Organ mass?

Free radical theory of aging is somewhat related to metabolic rate hypothesis.

But CRed animals may have less oxidative damage because of reasons other than reduction of metabolic rate.

Properties of isolated mitochondria are hard to measure reliably. He is suspect of evidence from isolated mitochondria.

Is free radical damage really associated w/ aging?

Evidence against free radical theory of aging: Mice lacking endogenous enzymatic anti-oxidants (SOD) suffer more oxidative damage, but don't live shorter lives.

There is quite a bit of evidence in favor of free radical theory of aging too.

So free radical importance still an open question.

Glucose hypothesis of aging:

Found same for insulin - less exposure as result of CR.

Found that both CR and AL animals were burning exactly the fuel mixture they were being fed - no preferential burning of fat.

But glucose burning per g body mass was the same for CR and AL.

So what Masaro and McCarter did study of animals w/ mutation in GLUT4. These animals had low plasma glucose, but same insulin level as normal mice. They didn't live any longer. Moral - glucose (or glycation) probably not the "bad guy" in aging. I.e. reducing glucose, but not reducing insulin, doesn't increase length of life.

So it is low insulin, rather than low glucose, that cause of CR benefits? Could be.

Next hypothesis - IGF-1 hypothesis

Dwarf mice seem to support this. Low IGF-1 in these animals associated w/ longer life.

CR definitely results in less insulin/IGF-1 signaling.

Very popular hypothesis today.

CR does other things:

CR protects against impact of stressors.

Example: percent body weight loss in mice subject to surgery a lot less in CRed animals than in AL animals. CR helps animals deal with stress.

Some of this better handling of stress may be due to reduce inflammatory response to stressors.

Found rats injected with toxins in their foot pad didn't get as more foot pad swelling.

Fewer rats die when subject to extreme temperature conditions when CRed. 16% vs. 75% survival of AL vs. CR when put in very hot room.

Masaro proposed hormesis hypothesis in 1998. Now its gaining popularity.

Hormesis Hypothesis:

Possible mechanism: Low intensity stressors upregulate defenses without damaging animal, and as a result "harden" the animal (put it in "protective mode") and help them live longer.

Can CR be considered a low intensity stressor?

Evidence: Corticosterone (stress marker) higher in CR rodents.

More evidence: Heat shock protein (hsp 70) induction which help animals deal with stress drops w/ age, and CR stops this decline. I.e. CRed animals more readily able to combat stress by releasing heat shock proteins than AL animals.

Summary of hormesis hypothesis:

1. Evolved to enable animals to survive in wild due to unpredictable and relative short food shortages.
2. Anti-aging action happens via long-term CR because this mechanism is constantly active.
3. Mechanism like Sirtuins may be explanation for how hormesis has its effects.

Michael Rae indicated that several hormesis studies suggest hormesis doesn't impact aging, like CR does.

We evolved when life was a "bitch". But life is cushy for us now. If we get back to a stressful life, we do better.

Q&A: