by SM Morgan
The media has been all of a flurry this last week over a paper by Mattison et al out of Maryland, reporting on the lifespan extension effects of caloric restriction in Rhesus monkeys – or more specifically, the lack of lifespan extension after caloric restriction in Rhesus monkeys.
The paper created such a stir because in the majority of model organisms, the restriction of access to food, without inducing malnutrition, is sufficient to cause a significant lengthening of life. To further complicate matters, a similar study reported earlier in 2009, by a different research group, found the monkeys did exhibit an extension of lifespan as a result of caloric restriction. And of course, the media loves the sensationalist view of something either making humans live forever – or denying them that opportunity.
Caloric restriction is the term given to the practice of limiting the ingested number of calories via diet to below that of which would be consumed freely, or ad libitum (access to as much food as you want, whenever you want). The research field, specifically investigating the extension of lifespan as a result of altered nutrition, and the mechanisms behind the control of it, has actually made a move more recently towards calling the phenomenon Dietary Restriction, to reflect a change in the knowledge. It is possible to induce this extension of lifespan effect by composing the diet of different macronutrients (so different levels of protein and carbohydrate) while maintaining the same calorie value, thus the calories themselves are seemingly not that important.
Traditionally the field has focused on the laboratory staples: nematode worms, fruit flies and house mice. The extrapolation of the research to more complex organisms, and primates in particular, is an exciting step forward. In this case, however, it might prove to be a tad premature.
This particular study used two groups of monkeys; old-onset monkeys, with whom the CR protocol was implemented later in life, at around 16 – 23 years of age, and young-onset monkeys for whom diet was restricted from an early age, unspecified and not included in the supplementary information. The only indication of the starting ages of this group is “young-onset (includes juvenile, adolescent and adult)”, and presumably younger than 16 – 23 years. The study was begun in 1987, obviously before any of the current knowledge was amassed, or modern techniques established to regulate dietary macronutrients. In terms of a longevity study in a long-lived organism, however – this shows remarkable foresight. The young-onset group of monkeys contains some still alive today, coming on 30 years of age, with the older-onset group having died out by ~40 years of age. These monkeys are older than I, and have been involved in lifespan research science for longer as well.
The numbers of animals in each category is fairly small, but with regards using primates as a research model, the expense for so many years must be extremely prohibitive. There were 22 young males eating normal food and 20 eating a restricted diet. 24 young females on normal food and 20 on restricted diet. In the older-onset group there were only 10 males eating normal food and 10 on a restricted diet, and 8 females on normal food and only 7 on restricted diet.
The analysis of the data (and some fancy statistics) to date shows males to be living longer than females, but within the sex groups there is no significant difference in lifespan – it doesn’t appear to matter what the monkeys are eating, they’re living for the same length of time. The study also investigated fasting serum triglycerides, cholesterol, and fasting serum glucose (Have a closer read of the paper if these measurements interest you).
The main point of contention, as I see it, is the disparity with the results of the WNPRC study, based in Wisconsin. This study showed in preliminary results (due to the entire cohort not being dead yet, and again some fancy statistics) that in Rhesus monkeys fed a 30% calorie restricted diet from adulthood onwards (7-14 years, and in this case falling into the current studies ‘young-onset’ group) survival was improved over that of control animals.
So what is different? Why are the studies showing different results? The paper is actually very good at addressing such questions, and has a very objective yet nicely argumentative tone. ‘These are the issues, look at this data compared to this data’ with no sweeping generalisations and making it a delight to read.
Firstly, the diets fed to the animals were different between studies. The current study used a natural ingredient-based diet, where the Wisconsin study used a purified, specified ingredient base, with added minerals and vitamins. The second biggest difference I find important is that the monkeys in the control group in the current study were not truly fed ad libitum, they were to some small degree restricted in their diet, though less so than the experimental restriction group. While this distinction prevented obesity in the current study, the group as a control was better in the Wisconsin study, where the monkeys could regulate their own intake and eat as much as they wanted.
The third difference which I find particularly notable is the origin of the monkeys in the studies. The current study included monkeys from both India and China, while the Wisconsin study had strictly Indian monkeys. This means the genetic diversity of the current studies group is greater than that of the Wisconsin study, and with such a great genetic influence on lifespan (becoming more apparent through more recent research), this is further muddying the waters of the lifespan results.
So my final impression? This is far less exciting than the articles in The Guardian, Discover Magazine, Nature, Science, WSJ and the rest, lead me to believe. I also think there are further confounding variables which go ignored in such a large-organism study. Did they monkeys have sufficient playtime/monkey-contact/sunlight? Did they suffer from monkey depression or anxiety? Do they suffer from the loss of traditional monkey society? Were the participants mated? The act of mating and the effort of full reproduction has drastic affects on lifespan. If so, were they allowed to stay with their mate/offspring? Was there forced or encouraged activity? Because you can restrict diet, but if one group is exercising more than the other, results would be affected regardless. What was the parental and prenatal situation like, and was it controlled between individuals? Did all the participants have ‘happy’ childhoods and normal early development? Especially in such an intelligent animal, I think such effectors on quality of life are relevant to quantity of life.
Don’t even get me started on such potential studies in humans.