No human CR?

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Hi All,

Will there be no CR in humans?

See the not pdf-available Medline citation and abstract below (1).

Rose, RM had previously written the below (2), with the additional reply (3).

1. Phelan JP, Rose MR.

Why dietary restriction substantially increases longevity in animal models but

won't

in humans.

Ageing Res Rev. 2005 Jul 23; [Epub ahead of print]

PMID: 16046282

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\

ct & list_uids=16046282 & query_hl=2

.... The apparent generality of the longevity-increasing effects of CR has

prompted

speculation that similar results could be obtained in humans. Longevity,

however, is

not a trait that exists in a vacuum; it evolves as part of a life history and

the

physiological mechanisms that determine longevity are undoubtedly complex.

Longevity

is intertwined with reproduction and there is a cost to reproduction. The impact

of

this cost on longevity can be age-independent or age-dependent. Given the

complexity

of the physiology underlying reproductive costs and other mechanisms affecting

life

history, it is difficult to construct a simple model for the relationship

between

the particulars of the physiology involved and patterns of mortality.

Consequently,

we develop a hypothesis-neutral model describing the relationship between diet

and

longevity. Applying this general model to the special case of human longevity

and

diet indicates that the benefits of caloric restriction in humans would be

quantitatively small.

2. Phelan JP, Rose MR.

Why dietary restriction substantially increases longevity in animal models but

won't

in humans.

Ageing Res Rev. 2005 Jul 23; [Epub ahead of print]

PMID: 16046282

Letters

Dietary Restriction in Drosophila

Dietary restriction is one of the few environmental interventions that generally

increases life-span (1). In their Report " Demography of dietary restriction and

death in Drosophila " (19 Sept., p. 1731), W. Mair et al. found that short-term

rather than long-term dietary restriction determined mortality rates in

Drosophila.

Dietary restriction was also found to affect only age-independent mortality, a

result found before (2). Mair et al. did not, however, shed much light on the

mechanistic basis of immediate changes in mortality rate arising from dietary

change. We believe that we can.

Dietary restriction tends to increase Drosophila life-span, reduce mortality

rate,

and reduce female fecundity drastically (3). As fecundity often has an

antagonistic

evolutionary relationship with longevity (4), diminished caloric intake may

reduce

costly physiological investment in reproduction, regardless of whether

reproduction

is occurring or not, and thereby reduce mortality.

We have some evidence for the existence of such a trade-off during abrupt

nutritional change. Chippindale et al. (3) found that reproduction shifted

upward

when additional food was supplied in mid-life and downward when food was reduced

[see fig. 3 in (3)]. This transition took about 3 days, in either direction,

about

the same magnitude of time as the 48-hour transition observed by Mair et al.

Chippindale et al. (3) also studied the short-term response of starvation

resistance

to a change in dietary regime. Starvation resistance is a major factor

determining

longevity in D. melanogaster (5-7) and is in turn determined by the total stored

calories in the fly (8). When dietary regime is abruptly changed, Chippindale et

al.

(3) found a rapid shift in starvation resistance that was the inverse of the

rapid

shift in fecundity. This also matched the known evolutionary antagonism between

starvation resistance and fecundity. Given the evidence linking starvation

resistance to longevity, starvation resistance must influence mortality rates.

In

sum, our interpretation of the effects of abrupt dietary change is that when

fewer

calories and nutrients are ingested, fecundity falls, increasing the storage of

calories, thereby reducing mortality rates, and conversely.

Furthermore, this interpretation can be extended to explain the findings of Mair

et

al. for both the increase and decrease in mortality rate in males and females

with

dietary change. That is, when caloric intake is increased, the storage of

calories

is reduced and reproductive activity increases, thereby increasing mortality

rates.

Conversely, when caloric intake is decreased, the storage of calories is

increased

and reproductive activity decreases, causing mortality rates to drop.

3. Rauser CL, Mueller LD, Rose MR.

Dietary restriction in Drosophila.

Science. 2004 Mar 12;303(5664):1610-2; author reply 1610-2. No abstract

available.

PMID: 15016980

Response

Rauser et al. suggest that the reduction in mortality rate in Drosophila in

response

to dietary restriction (DR) is caused by reduced fecundity and/or increased

stress

resistance.

Increased life-span in response to DR in diverse organisms is accompanied by a

reduction in daily and lifetime fecundity (1-3). The suggestion that this

reduction

in fecundity is causal in the extension of life-span under DR has been made

several

times previously (4-7), including in the Perspective accompanying our paper (8).

The

idea may be correct, but at present, there is no direct experimental evidence

for or

against it. Experiments in which costly aspects of reproduction are blocked

directly, and the effect on the response of life-span to DR examined, could

throw

some light on the issue.

Increased stress resistance has also frequently been shown to accompany

extension of

life-span in response to DR and has again previously been suggested to be causal

(9-14). As for the effects of fecundity, there is no experimental evidence, and

direct manipulation of the stress responses in DR and control animals could

prove informative.

Al Pater, PhD; email: old542000@...

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