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. 2011 Aug 3;14(2):154-60.
doi: 10.1016/j.cmet.2011.06.013.

Dietary restriction and aging: a unifying perspective

Matthew D W Piper  1 , Linda Partridge, David Raubenheimer, Stephen J Simpson
Affiliations

Dietary restriction and aging: a unifying perspective

Matthew D W Piper et al. Cell Metab. .

Abstract

Dietary restriction (DR) and mutations in nutrient signaling pathways can extend healthy life span in diverse organisms. Studying the interaction between these interventions should reveal mechanisms of aging, but has yielded some apparently contradictory results. A multidimensional representation of nutrition, called the geometric framework, can better describe the responses of life span and other traits, including metabolism, and can reconcile these apparent contradictions. We provide examples showing that it is more informative to analyze DR in terms of dietary balance and that dietary optimization for life span is critical for studies examining the biology of aging and other traits.

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Figures

Figure 1
Figure 1
The effects of protein and carbohydrate intake on response surfaces for lifespan and reproductive output of three insect species. Phenotypic response surfaces for longevity and reproductive output (eggs laid or in the case of male crickets, time spent singing to attract mates) are plotted for three insect species: the fruitfly Drosophila melanogaster, the Queensland fruitfly Bactrocera tryoni and the field cricket Teleogryllus commodus. Insects were given ad libitum access to one of 28 (Drosophila and Bactrocera) or 24 (Teleogryllus) diets varying protein to carbohydrate (P:C) ratio. Surface values increase from dark blue to dark red. Unbroken red lines show the dietary P:C that maximized the response variable; dotted lines indicate isocaloric intakes. Data re-plotted from (Lee et al., 2008) (Drosophila), (Maklakov et al., 2008) (field crickets), and (Fanson et al., 2009) (Queensland fruit fly). Figure from (Simpson and Raubenheimer, 2012).
Figure 2
Figure 2
Effect of nutritional balance on lifespan. Response surfaces for median lifespans of wild-type (A) and mutant flies (E) mapped onto intake estimates for carbohydrate and protein. Diets can be represented on the surface as lines (‘rails’) and consumption represented by distance from the origin. Thus, as an animal consumes a diet, its position in nutrient space moves along a dietary rail away from the origin. (A) Fitted lifespan response surface for wild-type Drosophila. Data from 22 diets in 5 published studies (adapted from (Lee et al., 2008)). The surface for the mutant (E) was created by transforming the data in (A) such that the lifespan peak is right-shifted to higher protein concentrations. The transformation applied was as follows: LM = LW - 3(LW.R/100) where: LM = median lifespan of mutant; LW = median lifespan of wild-type (Figure 1A); R = ratio of carbohydrate to protein in the diet. The surface was then normalised to the same range of lifespans as in wild-type flies and food intake left unchanged. The effect is that for a given level of carbohydrate intake there is a lifespan shortening cost for high dietary carbohydrate: protein ratios. This could be, for example, due to increased deposition of body fat. In addition to this cost, the mutants also gain a lifespan advantage with lower dietary carbohydrate: protein ratios. Together, these cause the lifespan peak to be right-shifted along the protein axis. Variation in the propensity to lay down body fat on high carbohydrate: protein diets is known to occur in insects (see (Warbrick-Smith et al., 2006)). Drosophila genotypes too vary in body fat; fatness confers advantages in some environments through resistance to starvation (e.g. (Ballard et al., 2008), and refs therein) and when energy is limited on low carbohydrate: protein diets. (B-D; F-H) Standard representation of median lifespan responses of flies to three different dietary restriction (DR) protocols. These plots are generated from the data in the GF plots. Each of the three differently coloured straight lines transecting the GF plots (Figures 2A & E) represents a range of nutrient intake levels for animals treated with one of three different DR interventions. Each of these nutrient intake lines is used as a different x-axis for a traditional DR plot. The lifespan responses to each DR treatment are the heat map values that lie along each of the coloured lines. Plotted lifespan values are colour matched to the nutrient intake lines for each DR intervention on the GF plot. (B-D; F-G) By restricting access to protein and/or carbohydrate, lifespan shows at least part of a typical ‘tent’-shaped response to DR: as nutrient(s) are restricted, lifespan increases to peak at intermediate concentrations, whereupon it decreases again with further restriction due to malnutrition. (H) For the same nutrient intakes as wild types in Figure 2D, the mutation modifies the lifespan response such that no variation is detected.
Figure 3
Figure 3
Mechanistic interpretations of how a gene mutation may interact with traditional DR interventions (redrawn from (Mair and Dillin, 2008)). (A) Independent: a mutant that is longer lived than the wild type for all levels of nutrient intake, including at the lifespan peak, is thought to extend life by a mechanism independent of DR. This is because the processes required to extend life by DR are assumed to be maximized in wild types at the point of the lifespan peak, meaning any further extension caused by the mutation must be due to additional, unrelated, processes. (B) DR Mimetic: a mutation that mimics DR is expected to right-shift all lifespan values to higher levels of food intake. Thus, the organism is more sensitive to malnutrition at low food concentrations and less sensitive to the lifespan shortening effects of high food. Importantly, because the mutation interacts with the pathways employed by DR, combining both interventions does not extend lifespan beyond the peak level achievable with DR alone. (C) Master Regulator: this mutation does not extend life beyond the maximum achievable by DR. However, mutating this gene completely blocks any lifespan response to DR, fixing lifespan either at a constitutively high (depicted) or low level. (D-F) Comparison of wild type and mutant flies to each of the three DR interventions illustrated in Figure 2. According to the definitions above, these modifications can be interpreted as the mutation being independent of (F), a mimetic of (G) or a master regular of (H) the mechanisms for lifespan extension by DR (see similarities to Figure 3A-C). An alternative explanation, gained from the GF perspective (Figure 2A & E), is that the mutation alters the ability of flies to cope with changes in nutrient balance. Because the maximum attainable lifespan across all nutrient combinations is unchanged between the genotypes, ageing may not be altered.
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References

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