The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 16 No. 10 • November 2013


Life Extending Natural Products Can Give Different Results When Fed Over An Animal’s Entire Lifetime as Compared to Fed At Just Specific Parts of the Lifespan

A new study1 reports that curcumin acts as a dietary restriction mimetic by increasing lifespan when administered during specific periods of the lifespan of Drosophila but find that whole life intervention is not always the most effective intervention. Basically, they report here1 that 4-phenyl butyrate (4PB), a life extending natural product, administered during the first 12 days of the adult lifespan was not as effective as feeding during the time period from 12 days to the end of life. The researchers identified the first 12 days as including a portion of the adult healthspan, while the period of 12 days to the end of life included the transition and senescent periods. The results of this and other studies looking at treatment with life extending materials at only specific periods of the lifespan are pointing to additional complications in interpreting how increases in lifespan are produced.

The researchers report that there is significant change (~23%) in genome wide transcript profiles with age in Drosophila, suggesting that gene-induced changes by treatments with putative life extending materials may not have the same effects at all life stages.1 They found that curcumin had beneficial effects in the normal lived Ra strain of Drosophila in that it increased longevity when administered in the developmental or health span stages, which (they suggest) could be due to systemic effects on the TOR complex, where reduced expression has been associated with life extending effects in studies with model organisms, but that curcumin had a negative effect on lifespan when administered over the entire adult lifespan or over the senescent stage only. They propose that this could be due to “an apparent curcumin-dependent accelerated neuromuscular degeneration observed in the legs of mid- and late-life treated animals.”

The authors conclude that life-time feeding may be responsible for the failure of curcumin to significantly extend the healthspan and delay the onset of senescence by studies in other labs.

In a different paper,2 researchers found that increased oxidative resistance induced in human MEF cells and in Drosophila by exposure to acute, chronic, and repeated oxidative stress had different effects on lifespan. “Regrettably, regimens of adaptation to both repeated and chronic stress that were successful for short-term survival in Drosophila nevertheless also caused significant reduction in life span for the flies.”2

The authors sum up their findings: “repeated MEF cell oxidant exposures seem to prevent adaptive stress responses if the interval between exposures is too short and/or if each exposure is at too high an oxidant level. In contrast, repeated cell exposures at 12-h intervals, especially at lower oxidant concentrations, seem to potentiate positive stress adaptations and extend the period of protection. Chronic oxidant exposure at low oxidant levels can actually potentiate and extend adaptive responses, but chronic exposure to higher oxidant levels prevents adaptation.” For the Drosophila melanogaster, repeated oxidative stress adaptation at intervals of 1 or 3 days is toxic but intervals of 7 days are tolerated in terms of [improved] short-term survival. Life span however, seems to be negatively influenced by all repeated stress adaptation regimens. Short-term survival is also negatively influenced by chronic oxidative stress adaptation at all levels.”2 “All repeated treatments appeared to have a negative long-term effect, because flies that were repeatedly exposed to H2O2 [hydrogen peroxide] had a shorter life spans than untreated flies. We also observed a progressive decline in Drosophila life span with frequency of H2O2 treatment.”2

These results indicate that there is a great deal yet to learn about the dose and timing of hormesis that results not only in short term resistance to stresses such as oxidative stress but increased lifespan, which would appear to require different processes that work over a long period of time.

Nevertheless, the results of these studies must be reconciled with others that found mild stresses to have anti-aging hormetic effects and appeared to show an effective approach to modulate aging.3 For example, in paper #3. researchers reported that a single heat-shock early in life extended longevity by 20% or more in C. elegans by decreasing initial mortality only, with the rate of increase of subsequent mortality (the Gompertz component) being unchanged. Worms were also exposed to multiple heat shocks3 in the study with each heat shock having a hormetic effect on lifespan but with the magnitude of each additional single heat-shock decreasing as the age of the animal increased.

References

  1. Soh et al. Curcumin is an early-acting stage-specific inducer of extended functional longevity in Drosophila. Exp Gerontol. 48:229-39 (2013).
  2. Pickering et al. Oxidative stress adaptation with acute, chronic, and repeated stress. Free Radic Biol Med. 55:109-18 (2013).
  3. See, for example, Wu et al. Multiple mild heat-shocks decrease the Gompertz component of mortality in Caenorhabditis elegans. Exp Gerontol. 44:607-12 (2009).

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