Staff: Professor John Speakman, Sharon Mitchell, Jacques Togo Student: Daniel Phillips MRes
Image: Calorie Restriction increases healthy lifespan in diverse range of animals from single cell, invertebrates and vertebrates. Reproduced from Fontana and Partridge 2015
Background
Calorie restriction (CR) is the only non-genetic manipulation of animals that reliably increases lifespan via an effect on the rate of ageing. CR animals also have improvements in the susceptibility to a wide range of pathological conditions including insulin resistance, type 2 diabetes and cancer. CR is therefore an important intervention modulating health span as well as lifespan. CR has been shown to be effective in a wide range of different species from yeast to non-human primates (Speakman, John R., Mitchell 2011). However, the CR effect is not universal. While a wealth of research on CR conducted in rodents report lifespan extension, a varying response to CR was found in 41 recombinant inbred mouse strains (ILSXISS) with a reduction in lifespan in a high proportion of the males and females on CR (Liao, Rikke et al. 2010). Of note CR also does not increase lifespan in house flies, something we plan to investigate further (Cooper, Mockett et al. 2004).
CR work on non-human primates raises the hope that CR may also be effective in humans.
The effects of CR are so convincing in animal studies that some people have already started to voluntarily restrict their intake in the hope that they too will increase their lifespans. Known as CRONies (Caloric Restriction with Optimal Nutrition) their goal is to live longer and healthier by restricting their diet by 10 to 25% fewer calories.
Dr. Roy Walford was one of the first to advocate CR as means to extend lifespan. Dr. Walford was one of the researchers that entered the Biosphere 2 project in Arizona where he spent 2 years in involuntary restriction. After he emerged, he continued to restrict his intake and wrote several books on the power of CR to increase lifespan. Dr. Walford was an authority in gerontology and nutrition, publishing numerous papers and the book “The Retardation of Aging and Disease by Dietary Restriction” together with Dr. Richard Weindruch.
In addition to these volunteer organisations the NIA in the US have also sponsored a randomised clinical trial to evaluate the effectiveness of CR in humans. The trial is called CALERIE (Comprehensive Assessment of the Long-term Effects of Reduced Intake of Energy). The CALERIE study is run across three sites, the Pennington Biomedical Research center in Baton-Rouge (PI: Eric Ravussin), The Jean-Meyer Nutrition research center at Tufts in Boston (PI Susan Roberts), and the School of Medicine at the Washington University in St louis (PI John Holloszy). The study is coordinated from Duke University . John Speakman is a member of the data safety and monitoring board for CALERIE. Recent publications from CALERIE provided evidence that some of the metabolic responses to CR measured in humans are similar to those observed in animals.
A key problem with CR is that despite many years of intensive research effort it remains unclear what the defining mechanisms are that mediate the specific health and longevity effects. In rodents it has been established that the extension of lifespan is directly and linearly related to the extent of restriction (Speakman, John R., Hambly 2007, Speakman, JR, Mitchell et al. 2016). This led to the prediction that the mechanisms which lead to increased lifespan via CR must also be linear.
Graph: The relationship between level of calorie restriction (CR) and lifespan
The relationship between % calorie restriction (CR) either with simultaneous protein restriction (PR) (grey points) or with no PR (black points), and the % increase in median lifespan relative to ad libitum fed animals. The data refer to various rat and mouse strains. The lines show the no intercept fitted regressions for the two data sets (dashed line for CR with no PR). (Speakman, JR, Mitchell et al. 2016)
Funding from the UK BBSRC (Do neuropeptides mediate the link between caloric restriction and life span extension? BB/G009953/1) allowed us to explore the graded effect of CR. The project involved exposing male C57BL/6 mice to graded levels of CR from 0 to 40% restriction. All of the mice, including the control animals at 0% restriction, were only fed during the hours of darkness. We also included an additional 24hr ad libitum group. Adult mice (5 months) were exposed to the CR for a period of 12 weeks before their responses are characterised. We have published 17 papers to date with topics ranging from body composition, endocrine, metabolic, body temperature, physical activity, transcriptomics to metabolomics.
Graph: Daily body mass (BM) (g) recorded over 2 weeks of baseline (BL) (-14 to 0) and 12 weeks of treatment comprising 12 or 24h ad libitum (AL) feeding and graded levels of caloric restriction (CR) from 10 to 40% (10CR, 20CR, 30CR and 40CR respectively). Data are presented as daily mean ı SEM (g). (Mitchell, Tang et al. 2015)
Graph: Hormonal changes measured in male C57BL/6 mice following calorie restriction (CR). Mice were fed 12 or 24 hrs ad libitum (12AL or 24AL) or calorie restricted (CR) by 10, 20, 30 or 40% (10CR, 20CR, 30CR and 40CR) for 3 months. Circulating levels of a) leptin, c) tumor necrosis factor (TNF)-α, d) insulin-like growth factor (IGF-1) and f) insulin. Significant hormonal relationships are shown between b) fat mass and leptin, e) structural tissues and IGF-1, g) vital organs and insulin and h) liver and insulin. Results are expressed as mean ı sem. Different letters denote significant differences between treatment groups. (Mitchell, Delville et al. 2015)
Hempenstall,S, Picchio,L., Mitchell,SE., Speakman,JR and Selman,C. Mechanisms of Ageing and Development 131(2) ,2010, 111-118. https://doi.org/10.1016/j.mad.2009.12.008
