CR and Body Temperature

[Guest guest]

Al posted an interesting paper discussing the effects of CR and

temperature on flies (below).

It is interesting that a higher environmental temperature for flies

" increases the rate of aging by inflicting permanent debilitation and

that thermal history is a major determinant of mortality "

What are the consequences for warm-blooded humans who have thermal

regulation systems? Dr. Walford mentions in BT120YD that high

temperature is a source of stress and that calorically restricted

humans will display lower body temperature (pp. 82, 163, 228).

Perhaps the one or two degree lowering of average body temperature

over many years by CR may play a role in longevity.

All this raises interesting questions:

1) should you raise the thermostat when you are cold?

2) should you participate in high-energy sports that raise your body

temperature?

3) should you work (or lie on the beach) in the hot sun?

According to the paper " Death occurs when the combined effects of risk

and damage are sufficiently great "

Food for thought.

Tony

Oops.. CR for thought ;-)

===

Mair W, Goymer P, Pletcher SD, Partridge L. Demography of dietary

restriction and death in Drosophila. Science. 2003 Sep

19;301(5640):1731-3. PMID: 14500985

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

ct & list_uids=14500985 & query_hl=61

Dietary restriction (DR) prolongs life-span and delays the onset of

many age-related declines in function (1–4). In Drosophila, DR is

applied by maintenance of adult flies on a food medium that contains

roughly 35% less yeast and sugar than standard laboratory medium (2,

5). Both mean and maximum life-span are increased under DR conditions

(5). Age-specific mortality is a measure of the instantaneous hazard

of death for an individual at a given age. Unlike survivorship

analysis, which is a cumulative measure, age-specific mortality allows

independent comparisons of vulner-ability to death at different ages

(6, 7). In Drosophila, chronic DR results in a delay in the onset of a

detectable aging-related increase in mortality (5). Once the mortality

increase is detected, however, it proceeds at roughly the same rate in

DR and control flies (5).

Interventions can lower adult mortality by slowing the accumulation of

the irreversible damage that is characteristic of aging (aging-related

damage), by reducing short-term vulnerability to death (risk), or by

some combination of the two (8). We can distinguish these hypotheses

experimentally for DR by examining the effect of past and current

nutritional conditions on age-specific mortality. This type of

approach has shown that, in Drosophila, increased reproductive

activity in males (8) and yeast deprivation in females (9) result in a

higher mortality that is entirely due to an increased risk of death.

In contrast, Mediterranean fruit flies (Ceratitis capitata) switched

from sugar only to sugar and yeast food were permanently affected by

their previous diet (10). If DR acts solely by slowing the

accumulation of aging-related damage, then the onset of DR would not

lead to a drop in mortality rate, because the damage would not be

reversed. However, DR would result in a slower subsequent accumulation

of aging-related damage and, hence, a less rapid subsequent increase

in mortality rate with age. If, instead, increased nutrient

availability introduces a higher risk of death, then removal of this

risk by DR would result in a sustained drop in the elevation of the

mortality trajectory relative to that of permanently fully fed

individuals. If DR increases life-span solely by reducing the

short-term risk of death, then the mortality rates of previously fully

fed individuals switched to DR would drop to the same levels as those

seen in same-age individuals subjected to DR throughout adulthood.

Hence, both hypotheses predict that the onset of DR at any age will

increase life-span. Under the damage hypothesis, the mortality

trajectory after the onset of DR has a lowered slope, whereas under

the risk hypothesis the mortality rate shows a sustained drop in

elevation. These hypotheses are not mutually exclusive.

To determine the importance of these two mechanisms of life-span

extension by DR in Drosophila, nutritional conditions were manipulated

and age at death was assessed in 7492 individuals. Age-specific

mortality trajectories for female flies subjected to DR from the onset

of adulthood showed the characteristic delay in the onset of

detectable aging-related mortality, compared to those maintained on

full feeding (Fig. 1A). When fully fed flies were switched to DR on

days 14 or 22 of adulthood, there was a rapid and complete reduction

in age-specific mortality to the levels seen in permanent DR flies

(Fig. 1A). Within 48 hours, the mortality of these switched cohorts

had declined to the level of flies maintained on DR throughout adult

life, and after this point the two mortality trajectories were

indistinguishable. Males showed a similar response (Fig. 2A).

These results demonstrate that age-specific mortality of the DR flies

depends only upon their age and their current nutritional status, with

past nutrition having no detectable effect. DR therefore lowered

mortality entirely as a consequence of a lower short-term risk of

death, and the accumulation of aging-related damage remained

unaffected. In reciprocal switches from DR to fully fed conditions,

mortality levels showed a rapid (within 48 hours) increase (Fig. 1B).

In females, subsequent mortality was reduced in the switched groups

compared to mortality of the permanently fully fed flies, and the

magnitude of this reduction was greater in the group that was switched

later. Long-term DR therefore either impeded the females' ability to

respond to full feeding or protected against its increased risk. Males

showed no such effect, and subsequent mortality was slightly higher in

individuals with a history of DR (Fig. 2B).

We performed a similar experiment examining the effect of current and

past experimental temperature on mortality in Drosophila. In sharp

contrast to the effects of DR, lowered temperature, which also

increases life-span in ectotherms (11, 12), reduced the accumulation

of aging-related damage. Flies cultured at a lower temperature

exhibited a reduction in the slope of the mortality trajectory, rather

than a delay in the time when aging-related mortality could first be

detected (Fig. 3A), as has been previously reported (13). When flies

were switched from 27°C to 18°C environments (Fig. 3A), the increased

mortality driven by life at a higher temperature persisted in the

switched flies compared to the 18°C control flies. This effect of

thermal history was greater the later the age at which the switch was

made. After the switch, the subsequent rate of increase in mortality

with age reflected the new temperature: It was lower in the switched

flies currently at 18°C than in the flies permanently at 27°C. Flies

switched from high to low temperature at various adult ages therefore

showed slower demographic aging. The reciprocal switch, from 18°C to

27°C (Fig. 3B), produced similar findings: The lower mortality seen in

flies at the lower temperature persisted in the switched flies, and to

a greater extent the later the switch was made. After the switch, the

rate of increase in mortality rate with age rose to become

indistinguishable from that seen in flies kept permanently at the high

temperature. These results demonstrate that higher temperature

increases the rate of aging by inflicting permanent debilitation and

that thermal history is a major determinant of mortality. This is in

sharp contrast to the effect of DR on mortality, in which there is no

memory of past feeding.

These findings support the hypothesis that DR in Drosophila extends

life-span solely by reducing the short-term risk of death. DR and

control flies accumulate irreversible, aging-related damage at the

same rate, but the accumulated damage produces a detectable increase

in the death rate at later ages in the DR flies. Death occurs when the

combined effects of risk and damage are sufficiently great, and a

lowering of risk by DR holds the flies below this death threshold for

longer, in some support of the set-point model of life-span extension

by DR (14). The crucial criterion for determining the roles of reduced

risk and damage in the extension of life-span is the response of the

mortality trajectory to switches between high- and low-mortality

regimes. Although other interventions such as mutations in the insulin

and insulin-like growth factor signaling pathway have been shown to

extend life-span in C. elegans, Drosophila, and mice (15–18), it is

not clear if these reduce risk, the rate of accumulation of

aging-related damage, or both. DR initiated during middle age in

mammals increases subsequent life-span (19, 20), but this result is

consistent with either the damage or risk hypothesis. The critical

experiments in mammals have yet to be done.