The Evolution of Research on Ageing and Nutrition

Abstract

N the seminal 1935 publication, McCay and colleagues (1) reported that calorie restriction increased lifespan of white rats. Their primary hypothesis was that “a slow rate of growth results in an increased lifespan.” In order to slow the rate of growth, the food provided to the rats was down-titrated to maintain slow growth and a low body weight, whereas the control rats had unlimited access to food. This work has been cited over 1,300 times and has led to the dogma that calorie restriction is the most robust interven-tion to delay ageing. The conclusion has been replicated across taxa (2), and there are health benefits—if not longev-ity extension—seen in humans (3) and nonhuman primates (4). The relationship between calorie intake and ageing has led to important insights into the molecular switches (tar-get of rapamycin, sirtuins, insulin/IGF-1/growth hormone, 5′ adenosine monophosphate-activated protein kinase) that interface between dietary intake and those cellular pro-cesses (mitochondrial function, autophagy, DNA repair, oxidative stress) that influence the rate of ageing (5).Albert Einstein has been attributed with the comment that “everything should be as simple as it can be, but not simpler.” Is it too simple to conclude that just a reduction in energy intake delays ageing? Indeed there now are bur-geoning numbers of studies that show there is considerable complexity in the effects of various nutritional interventions on ageing. For example, there have been many attempts to compare the effects of calorie restriction against reduction of various components of the diet such as the macronutri-ents (fat, carbohydrates, and protein). One of the very first of these studies was undertaken by McCay who in 1928 reported a study where trout were fed many diets differing in micro- and macronutrient content. They found that those trout that lived the longest were fed the low-protein diets (6). Subsequent studies on protein restriction have reported mixed results but generally concluded that it is energy restriction rather than specific macronutrients that impact on ageing (7).However, one complication of only manipulating the ratio of protein to other nutrients in diets is that some animals use compensatory feeding when the balance of nutrients in their food is not optimal. The protein content of food is par -ticularly influential in driving energy intake and appetite. In a response called “protein leverage,” animals including humans tend to overconsume calories when presented with a low-protein diet, and vice versa (8,9). Therefore, simply reducing the amount of protein in the diet may not have any impact on protein intake if animals have adequate access to food—they will simply increase their total food until they achieve their protein target. Therefore, it is important that studies carefully measure and report food intake, particu-larly in ad libitum-fed animals.One approach that has been utilized to deconvolute the complex interactions between macronutrient intake and ageing is the geometric framework. This analytical method allows for the examination of the independent and inter-active effects of multiple nutritional components (energy, fat, carbohydrate, protein) on outcome data such as ageing (8,10,11). When this geometric framework method was applied to nutritional experiments in