Yes, I read the paper. And you are wrong - that’s OK, I’ve studied CR for decades, so that’s my advantage. There is a lot of subtle stuff going on. CR is less effective or not effective, not in animals that have “better” genes, but in animals that are already somewhat optimised for longevity. As an example, it is speculated that the reason humans likely benefit little from CR, is because we as a species are already optimised for longevity, so CR doesn’t bring much to the table. It’s not that the genes of any particular human are good or bad that makes CR not effective in humans, it’s that the whole species is less suited to a CR intervention.
CR is a survival modality that was preserved evolutionarily to cope with food scarcity. The more a species was prone to encounter food scarcity, the more useful CR was, and the stronger its effects in that species. But conversely, the less energy scarcity a species had in its environment of operation, the less needed, and so the less developed was the CR response. Mice and rats are excellent models for CR. Mice live 3 years at best, even less with predation in the wild. And natural events in their environment - droughts, floods, fires, vegetation disease wiping out a food source etc., are a regular ocurrance to deal with. A bad year of drought or such is A FULL 30% of a mouse lifespan. If the mice were not able to survive food scarcity for a full 30% of their lifespan, they would die out as a species. So CR which allows them to survive with little food for a full 30% of their life is a very powerful evolutionary advantage. The worse the famine - the more extreme the CR - the longer they have to survive. That’s how you get mice on increasingly harsh CR live increasingly long by 30%, 40%, 50% and so on. They must survive worse and worse famines.
Contrast that with humans. First of all, humans as a species are very good at eating everything and finding food everywhere. For early humans in our evolutionary past, we were never in as harsh situations of food scarcity as species such as mice - we are more resourceful, eat more broadly omnivorously, can relocate and so on. A flood happens, or a disease wipes out the vegetation we live on, we are not in a disastrous situation like a mouse is. We can travel great distances, and we can bring down a mammoth. We don’t need CR as badly, so we never preserved as much of a response to it. Our ancestors would never find themselves in a situation of food scarcity - flood, fire, drought, disease - that lasts for 30% of our lifespan, for decades. So quite naturally, our response to food restriction, DR, CR is going to be mild, it will not give us a 40% lifespan extension, because in our evolution we at most had temporary food scarcity, so our response to CR, DR is equally small, temporary, fit for purpose, not for decades.
It is not because mice have bad genes and humans good genes that CR works great in mice and not much in humans. It is down to what the CR is good for in a given species from an evolutionary point of view.
Now back to mice. You referenced “long lived mice”:
“For instance, there was another study in mice showing that long-lived mice (with “good” genes) didn’t benefit from CR.”
Fundamentally, no. There are no “good” longevity genes - these are different mice with different genetic profile than lab mice. Same as you would not compare “good” human long-lived genes to “bad” short-lived mouse genes. But in mice it is more complicated, because they are the same species - still look at dogs, same species, but a terrier will live much longer than a great dane. With lab mice vs wild type mice it is even more complicated, because lab mice were selected for a variety of lifespan pressures compared to wild type. Apples and oranges. The CR experiments that you are referencing, were the Austed studies in wild type mice. There is a lot of background to understand the context. CR has a wide effect on an organism, such as a mouse. There is of course the more efficient use of energy. But there are many other effects, such as reorienting from reproduction to preservation - it makes sense not to have youngsters that need to be fed when there is a famine. Your energy output actually increases with CR in distinct ways, there is more movement and food seeking behavior, there is less need for sleep - makes sense for the animal to be able to forage more intensely and longer for scarce food. CR sharpens all the senses - makes sense to be able to find scarce food. And so on. It’s quite complicated to compare wild type mice for response to CR with laboratory mice with completely different genes that respond to lab conditions over generations, see below.
Here is the Austed et al study - it is very instructive:
"Summary
To investigate whether mice genetically unaltered by many generations of laboratory selection exhibit similar hormonal and demographic responses to caloric restriction (CR) as laboratory rodents, we performed CR on cohorts of genetically heterogeneous male mice which were grandoffspring of wild-caught ancestors. Although hormonal changes, specifically an increase in corticosterone and decrease in testosterone, mimicked those seen in laboratory-adapted rodents, we found no difference in mean longevity between ad libitum (AL) and CR dietary groups, although a maximum likelihood fitted Gompertz mortality model indicated a significantly shallower slope and higher intercept for the CR group. This result was due to higher mortality in CR animals early in life, but lower mortality late in life. A subset of animals may have exhibited the standard demographic response to CR in that the longest-lived 8.1% of our animals were all from the CR group. Despite the lack of a robust mean longevity difference between groups, we did note a strong anticancer effect of CR as seen in laboratory rodents. Three plausible interpretations of our results are the following: (1) animals not selected under laboratory conditions do not show the typical CR effect; (2) because wild-derived animals eat less when fed AL, our restriction regime was too severe to see the CR effect; or (3) there is genetic variation for the CR effect in wild populations; variants that respond to CR with extended life are inadvertently selected for under conditions of laboratory domestication."
And even in lab mice, the opposite is true for what you claim. It is the mice with “good” genes that live longer on CR, respond better to CR, than mice with bad genes. The mice which responded better to CR were superior genetically, because they could preserve weight with less food, had better immune systems to start with, and were more resilient to stress in general and the stress of CR.
Regarding drugs, yes, there are always arguments along the line of a drug of course prolonging the life of a sick individual (maybe due to bad genes), but not needed by a healthy individual (maybe one with good genes). But we are discussing who responds to a drug - who has genes that are “good” because they allow a good response to a drug, not whether the individual has good or bad genes in general. A sick person with “good” responsive genes to a drug, will live longer than an equally sick person who has “bad” gene responders to the same drug.
