Now, to be fair, the authors couldn’t have collected baseline data for some of the experiments that they reported this way, because doing so would kill or seriously harm the animal; the brain tissue studies immediately above are an example of this. But (a) they could have collected such data from animals the same age as the metformin-treated animals at baseline; and (b) they could have collected baseline data on all the noninvasive or minimally-invasive outcomes, such as cognitive function, periodontal disease, and others.
It’s unfortunately not uncommon for researchers doing rodent aging studies to fail to collect baseline data before starting an intervention and rely on a young control group for comparison. While this practice has the same broad problems in mice as it does in monkeys, the potential for scientists to fool themselves in the process is greatly reduced in mouse studies. That’s because of the high level of control that scientists typically have over the animals before they begin the experiment. For instance, they often use a strain of mice (such as the famous C57Bl/6) that is so thoroughly inbred that their genes match up in homozygous pairs, so there’s no room for genetic variation to imbalance the two groups. And they normally acquire all the animals in a study from a single professional mouse-breeding facility like The Jackson Labs or Charles River, where all the animals are bred, housed, fed, and kept free of germs under uniform conditions, with the same climate control and the same daily lights on/lights off cycle. This again minimizes the potential for variations among the animals that pre-exist the treatment to create the illusion that the treatment had some effect that it didn’t.
Accordingly, it’s standard scientific procedure to state in a paper exactly where the investigators got their animals, at what age, how they were fed and kept, and other important details. For instance, in an important rapamycin paper by Alessandro Bitto and Matt Kaeberlein:
All lifespan and healthspan experiments were performed on 19–20 month old C57BL6/JNia obtained from the National Institute on Aging Aged Rodent Colony. A separate cohort of C57BL6/J ranging from 17 weeks to 100 weeks of age was obtained from the Harrison lab at the Jackson Laboratory for histological analysis of SFB. Animals were housed in individually ventilated cages (Allentown, Allentown, NJ) containing corncob bedding (Andersons, Maumee, OH) and nestlets. Mice were fed irradiated Picolab Rodent Diet 20 #5053 (Lab Diet, St. Louis, MO). Animals were maintained in a specific pathogen free facility within a Helicobacter spp.-free room. Mice were housed in groups (5 per cage at a maximum) and aggressive male mice were isolated to prevent fighting. Mice were acclimatized at least two weeks before onset of experiments. Mice were inspected daily, and medicated for non-life threatening conditions as directed by the veterinary staff
Now you would think that for a study involving an animal much more closely related to humans than mice are, the researchers who did the cynomolgus metformin study would have been at least equally painstaking in sourcing and documenting the background and treatment of their animals. Well, you’d be wrong:
In this study, all male cynomolgus monkeys originated from Southeast Asia. Prior to long-term metformin treatment, monkeys had no clinical or experimental background, which could impact physiological aging or heighten sensitivity to diseases. The monkeys were kept in a clean breeding room with 25°C temperature and a 12-12 hours (h) light-dark cycle at Beijing Institute of Xieerxin Biology Resource, a Laboratory Animal Care accredited facility, fully compliant with all applicable local regulations pertaining to animal experiments. Monkeys were fed three meals and had free access to water.
“[A]ll male cynomolgus monkeys originated from Southeast Asia”? That’s all the provenance we get? Were they from Cambodia, Vietnam, Singapore, Myanmar …? Did they come from a scientific animal facility with long experience caring for cynomolgus monkeys, or from other scientists’ labs, or private breeding centers focused on the exotic pet trade, or zoos, or were they captured in the wild, or …? Did they acquire all the animals from the same source, or from two or more different sources? “Fed three meals”? I presume this means daily. What were they fed, exactly? We don’t know — though we do know that whatever it was made them obese and diabetic. And so on.
And to repeat: there were only six animals in each group, and there is no record of random assignment! So what if (for instance) most of the animals came from a reputable and humane monkey facility, but two animals that the researchers put into the control group were from somewhere that gave them no cognitive or social stimulation, or a nutrient-poor diet, or where there was lead in the drinking water, or where the breeding stock suffers some genetic defect that affected their health or intelligence?
Any such differences in background between the animals assigned to each group would skew the results. This issue also emerged as a potential problem in the NIA’s nonhuman primate CR study, in which some animals were obtained from a research colony in mainland China by way of the Texas Primate Center, but others were animals previously used for military research by the US Army in Maryland. At least in that case, the NIA researchers were transparent about their monkeys’ diverse and somewhat unsavory origin; for this metformin study, we get nothing but broad geography, embracing twelve different nations plus parts of China itself. Absent baseline testing, a larger number of animals, and random group assignment, this lack of provenance makes all of their inter-group comparisons fraught.
And in addition to its potential contribution to the very strong anti-obesity effect of metformin in this study (discussed above), an additional problem with administering metformin via the drinking water is that it makes it likely that the monkeys given metformin could tell that there was something not quite right about their water, causing them to behave differently. (Yes, animals can be subject to placebo effects, and nonhuman primates are closer to human intelligence than rats or dogs). By contrast, the control group did not get any kind of placebo treatment: they just got non-treated water to drink. So we can’t discount the apparent effects of metformin being a species of placebo or Hawthorne effect, either.
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- Source: https://www.sens.org/monkeying-with-clocks-metformin/