Phelan, J. P. & Rose, M. R. Why dietary restriction substantially increases longevity in animal models but won't in humans. Ageing Res. Rev. 4, 339-350

Life Sciences Core Curriculum Program, UCLA, Los Angeles, CA 90095-1606, USA.
Ageing Research Reviews (Impact Factor: 4.94). 09/2005; 4(3):339-50. DOI: 10.1016/j.arr.2005.06.001
Source: PubMed


Caloric restriction (CR) extends maximum longevity and slows aging in mice, rats, and numerous non-mammalian taxa. 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.

1 Follower
4 Reads
  • Source
    • "A comparative study (Blagosklonny & Hall 2009) has suggested that the link between growth and senescence is nutritional in nature. Dietary restriction, involving decreased nutritional intake, has been reported to improve health and result in longer life span in animals (Weindruch et al. 1986; but see Phelan & Rose 2005; Mattison et al. 2012). Plant growth is limited by cell division, which depends on water turgor and mineral availability. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 1. Senescence, the physiological decline that results in decreasing survival and/or reproduction with age, remains one of the most perplexing topics in biology. Most theories explaining the evolution of senescence (i.e. antagonistic pleiotropy, accumulation of mutations, disposable soma) were developed decades ago. Even though these theories have implicitly focused on unitary animals, they have also been used as the foundation from which the universality of senescence across the tree of life is assumed.2. Surprisingly, little is known about the general patterns, causes and consequences of whole-individual senescence in the plant kingdom. There are important differences between plants and most animals, including modular architecture, the absence of early determination of cell lines between the soma and gametes, and cellular division that does not always shorten telomere length. These characteristics violate the basic assumptions of the classical theories of senescence and therefore call the generality of senescence theories into question.3. This Special Feature contributes to the field of whole-individual plant senescence with five research articles addressing topics ranging from physiology to demographic modelling and comparative analyses. These articles critically examine the basic assumptions of senescence theories such as age-specific gene action, the evolution of senescence regardless of the organism's architecture and environmental filtering, and the role of abiotic agents on mortality trajectories.4. Synthesis. Understanding the conditions under which senescence has evolved is of general importance across biology, ecology, evolution, conservation biology, medicine, gerontology, law and social sciences. The question ‘why is senescence universal or why is it not?’ naturally calls for an evolutionary perspective. Senescence is a puzzling phenomenon, and new insights will be gained by uniting methods, theories and observations from formal demography, animal demography and plant population ecology. Plants are more amenable than animals to experiments investigating senescence, and there is a wealth of published plant demographic data that enable interpretation of experimental results in the context of their full life cycles. It is time to make plants count in the field of senescence.
    Journal of Ecology 05/2013; 101(3):545-554. DOI:10.1111/1365-2745.12089 · 5.52 Impact Factor
  • Source
    • "There have been numerous qualitative papers discussing the universality and ⁄ or specificity of the life-extending effect of DR across species (Partridge & Brand, 2005; Phelan & Rose, 2005; Le Bourg & Rattan, 2006; Mair & Dillin, 2008; Le Bourg, 2010). Our meta-analytic approach goes significantly beyond these verbal assessments, however, and shows that, given the right dietary conditions, DR could extend lifespan of any species, although the effect may be modulated by important factors such as sex. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dietary restriction (DR) extends the lifespan of a wide range of species, although the universality of this effect has never been quantitatively examined. Here, we report the first comprehensive comparative meta-analysis of DR across studies and species. Overall, DR significantly increased lifespan, but this effect is modulated by several factors. In general, DR has less effect in extending lifespan in males and also in non-model organisms. Surprisingly, the proportion of protein intake was more important for life extension via DR than the degree of caloric restriction. Furthermore, we show that reduction in both age-dependent and age-independent mortality rates drives life extension by DR among the well-studied laboratory model species (yeast, nematode worms, fruit flies and rodents). Our results suggest that convergent adaptation to laboratory conditions better explains the observed DR-longevity relationship than evolutionary conservation although alternative explanations are possible.
    Aging cell 01/2012; 11(3):401-9. DOI:10.1111/j.1474-9726.2012.00798.x · 6.34 Impact Factor
  • Source
    • "The ability of individual genes and pathways to affect CR is a major area of research with many potential human applications (Bishop and Guarente, 2007). Given the heterogeneity of human populations, it is unlikely that CR will have the marked longevity benefits in humans that it has in rodents, in particular for those individuals already on a relatively healthy diet (de Grey, 2005; Phelan and Rose, 2005). In fact, CR in wild-derived mice, which, unlike typical laboratory strains, are genetically heterogeneous, does not alter average lifespan even if it increases maximum lifespan (Harper et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aging is the major biomedical challenge of this century. The percentage of elderly people, and consequently the incidence of age-related diseases such as heart disease, cancer, and neurodegenerative diseases, is projected to increase considerably in the coming decades. Findings from model organisms have revealed that aging is a surprisingly plastic process that can be manipulated by both genetic and environmental factors. Here we review a broad range of findings in model organisms, from environmental to genetic manipulations of aging, with a focus on those with underlying gene-environment interactions with potential for drug discovery and development. One well-studied dietary manipulation of aging is caloric restriction, which consists of restricting the food intake of organisms without triggering malnutrition and has been shown to retard aging in model organisms. Caloric restriction is already being used as a paradigm for developing compounds that mimic its life-extension effects and might therefore have therapeutic value. The potential for further advances in this field is immense; hundreds of genes in several pathways have recently emerged as regulators of aging and caloric restriction in model organisms. Some of these genes, such as IGF1R and FOXO3, have also been associated with human longevity in genetic association studies. The parallel emergence of network approaches offers prospects to develop multitarget drugs and combinatorial therapies. Understanding how the environment modulates aging-related genes may lead to human applications and disease therapies through diet, lifestyle, or pharmacological interventions. Unlocking the capacity to manipulate human aging would result in unprecedented health benefits.
    Pharmacological reviews 11/2011; 64(1):88-101. DOI:10.1124/pr.110.004499 · 17.10 Impact Factor
Show more