Since 1935, scientists have known that putting rodents on very low calorie diets extends their lifespans. Scores of studies since then have shown that such calorie restriction (CR) can extend lifespan across species in a way suggesting it delays the onset of diseases of aging, extending healthspans (the proportion of life spent in good health) as well as lifespans. But, as detailed in my book, CR hasn’t extended lifespan in all species, nor has it worked in certain strains of rodents. In the latest study on the topic, it failed to extend lifespan in a long-term study in rhesus monkeys at the National Institute on Aging (NIA). The finding conflicts with results of another long-term CR study in rhesus monkeys at the Wisconsin National Primate Research Center in Madison, which showed that CR significantly improved late-life health in the primates; the Wisconsin study also offered evidence, though it wasn’t conclusive, that CR can extend lifespan in monkeys.
What all this means is that CR is probably more like medicine than magic. That is, almost all medicines work well for some individuals while doing little or nothing for others. Fewer than half of people put on antidepressants respond to them. And I can testify from personal experience that my genotype is virtually immune to Tylenol’s pain-killing effect.
Similarly, the latest study on CR has underscored that it doesn’t have a nearly magical ability to completely override the effects of different mixes of gene variants in the cohorts of experimental animals used in different studies and of subtle differences in experimental conditions that can lead to wildly different results in studies that supposedly test the same hypothesis. In other words, it seems that CR works quite well in certain species, certain genotypes within species, and certain environmental contexts, but not so well, or not at all, in others. This isn’t news, by the way. Various studies have shown that CR doesn’t work, for example, in medflies, houseflies, butterflies, and certain spiders, yet it has been shown to work in species ranging from protozoans to dogs—and in certain spiders. Further, its lifespan-extending effect in rats is generally greater than in mice, and it tends to boost lifespan more in mouse strains that aren’t inbred versus the inbred ones often used in research.
The devil is always in the details in science, and unfortunately there was no space in newspaper reports to spell out all the important details the newly reported study on CR, published by Nature. And a number of the study’s data points that didn’t make the cut in the initial media reports were quite interesting because they suggested there was something rather unusual about the genotypes of the particular cohort of monkeys in the NIA study, the experimental conditions of the study, or both of those factors—an indication that the NIA study, while carefully executed and important, may not have yielded the most representative results on CR in primates.
–In the NIA study, males in both the CR and control groups enrolled in the study after midlife lived significantly longer than females: Fifty percent of the females died after 27.8 years, while it took 35.4 years for the males to get to the 50% survival point. Indeed, the survival curves for the two sexes in the “late-onset group” showed a surprising and dramatic parting of the ways between males and females around age 27, the median age of survival for this species—as the animals entered their later years, males in both the control and CR groups showed a pronounced tendency to survive longer than females. This gender gap in longevity is just the opposite of the usual pattern—females generally outlive males in primates and other “higher” animals. For example, female macaques live on average about eight years longer than males, at least in the wild; U.S. life expectancy for men is 75.6, and for women it is 80.8.
–CR’s positive effects on biomarkers of health were also greater in the male monkeys in the late-onset group. For example, cholesterol and fasting glucose levels were significantly lower only in the CR males, suggesting they were at lower risk of heart disease, diabetes and other diseases of aging. Only the males on CR had somewhat lower triglyceride levels, another indicator of diminished heart risk. Males but not females on CR in the late-onset group also appeared to have experienced significantly less oxidative stress than controls; that indicates the males’ tissues were less injured by destructive molecules called free radicals, an ongoing form of molecular damage that many scientists believe is a key contributor to aging. This overall greater benefit on markers of health in males versus females may be another sign that there was something unusual about the genotypes or experimental conditions in this study. In contrast, in a landmark 2009 study showing that the drug rapamycin extends lifespan in mice in a way reminiscent of calorie restriction, females’ maximum lifespans were extended by 14%, while that of males was extended by 9%.
–Telling details related to CR’s effects on disease risks also got short shrift. For example, there were zero cases of cancer among monkeys put on CR at younger ages in the NIA study. (They were first put on CR between ages 1 and 14.) In contrast, in five of six cases of cancer among monkeys put on the control diets at younger ages, tumors were deemed to be the cause of death. Thus, as reported in many previous calorie restriction studies in mammals, CR from early in life potently reduced the risk of tumors in the NIA study. And there was a plainly visible trend toward later onset of five major diseases of aging in the young-onset CR group (cancer, diabetes, arthritis, diverticulosis, and cardiovascular disease) that narrowly missed qualifying as a statistically significant result—the P value for this difference was 0.06. (P values of 0.05 or less are considered statistically significant.) In sum, the NIA study suggested that CR improved late-life health in the monkeys, but the effect was modest and gender-specific.
–In a photograph of two 27-year-old monkeys from the NIA study that appeared in Nature, one on CR and one on the control diet, the CR animal looks a lot younger than its peer: The control monkey shows manifest signs of facial skin sagging and a hunched-back look compared to the svelte CR monkey. Interestingly, a similarly striking cosmetic difference was manifest in the Wisconsin study on CR in this species. Unfortunately, neither study provided data on markers of skin aging and other factors related to the cosmetic effects of aging.
The NIA study’s monkeys were descended from lines that came from China and India, while the conflicting Wisconsin study on CR in rhesus monkeys used animals from India alone. Thus, there may well have been significant genetic differences between the animals used in the studies.
The two studies’ dietary regimens were also quite different in several respects. Sucrose made up 28.5% of the Wisconsin diet, but only 3.9% of the NIA diet. The Wisconsin control monkeys were allowed to eat somewhat more than the NIA controls. Protein in the NIA diet came from wheat, corn, soybean, fish and alfalfa meal, while it came only from lactalbumin in the Wisconsin study. The NIA diet also included antioxidants and omega-3 fatty acids that weren’t included in the Wisconsin diet. And the control NIA animals were “supersupplemented” with vitamins and minerals compared with the study’s animals on CR, according to the Nature report; in contrast, the controls in the Wisconsin study didn’t receive extra vitamins and minerals. All these dietary factors potentially gave a boost to the NIA controls’ health as they aged, which might have contributed to the fact that they were about as healthy and long-lived as the monkeys on CR in the study.
Finally, it’s important to note that the NIA study was reported before its results on CR’s effect on maximum lifespan are available. This matters because extension of maximum lifespan is a much better indicator of an anti-aging effect than is extension of average or median lifespan—the latter are often affected by factors unrelated to aging, such as fatal infections early in life. And past studies indicate that it is entirely possible for CR to exert anti-aging effects, as measured by maximum lifespan and mortality curves, while having no effect on average or median lifespan. In a 2006 study in mice descended from wild mice captured in Idaho, for example, CR had no significant effect on average lifespan yet greatly lowered the risk of late-life cancer and increased maximum lifespan by 14%. The study suggested that in such mice, CR increased early-life mortality for some reason but exerted an anti-aging effect in mice that survived the early period of risk.
In sum, the NIA study is important because it underscored CR’s context-specific effect and shed some light on the particular conditions that tend to support calorie restriction’s anti-aging effect in primates—not because this single study overturned the general pattern that has been observed in over 75 years of studies in mammals on CR.
On Calorie Restriction, Monkeys, Magic and Medicine
Since 1935, scientists have known that putting rodents on very low calorie diets extends their lifespans. Scores of studies since then have shown that such calorie restriction (CR) can extend lifespan across species in a way suggesting it delays the onset of diseases of aging, extending healthspans (the proportion of life spent in good health) as well as lifespans. But, as detailed in my book, CR hasn’t extended lifespan in all species, nor has it worked in certain strains of rodents. In the latest study on the topic, it failed to extend lifespan in a long-term study in rhesus monkeys at the National Institute on Aging (NIA). The finding conflicts with results of another long-term CR study in rhesus monkeys at the Wisconsin National Primate Research Center in Madison, which showed that CR significantly improved late-life health in the primates; the Wisconsin study also offered evidence, though it wasn’t conclusive, that CR can extend lifespan in monkeys.
What all this means is that CR is probably more like medicine than magic. That is, almost all medicines work well for some individuals while doing little or nothing for others. Fewer than half of people put on antidepressants respond to them. And I can testify from personal experience that my genotype is virtually immune to Tylenol’s pain-killing effect.
Similarly, the latest study on CR has underscored that it doesn’t have a nearly magical ability to completely override the effects of different mixes of gene variants in the cohorts of experimental animals used in different studies and of subtle differences in experimental conditions that can lead to wildly different results in studies that supposedly test the same hypothesis. In other words, it seems that CR works quite well in certain species, certain genotypes within species, and certain environmental contexts, but not so well, or not at all, in others. This isn’t news, by the way. Various studies have shown that CR doesn’t work, for example, in medflies, houseflies, butterflies, and certain spiders, yet it has been shown to work in species ranging from protozoans to dogs—and in certain spiders. Further, its lifespan-extending effect in rats is generally greater than in mice, and it tends to boost lifespan more in mouse strains that aren’t inbred versus the inbred ones often used in research.
The devil is always in the details in science, and unfortunately there was no space in newspaper reports to spell out all the important details the newly reported study on CR, published by Nature. And a number of the study’s data points that didn’t make the cut in the initial media reports were quite interesting because they suggested there was something rather unusual about the genotypes of the particular cohort of monkeys in the NIA study, the experimental conditions of the study, or both of those factors—an indication that the NIA study, while carefully executed and important, may not have yielded the most representative results on CR in primates.
–In the NIA study, males in both the CR and control groups enrolled in the study after midlife lived significantly longer than females: Fifty percent of the females died after 27.8 years, while it took 35.4 years for the males to get to the 50% survival point. Indeed, the survival curves for the two sexes in the “late-onset group” showed a surprising and dramatic parting of the ways between males and females around age 27, the median age of survival for this species—as the animals entered their later years, males in both the control and CR groups showed a pronounced tendency to survive longer than females. This gender gap in longevity is just the opposite of the usual pattern—females generally outlive males in primates and other “higher” animals. For example, female macaques live on average about eight years longer than males, at least in the wild; U.S. life expectancy for men is 75.6, and for women it is 80.8.
–CR’s positive effects on biomarkers of health were also greater in the male monkeys in the late-onset group. For example, cholesterol and fasting glucose levels were significantly lower only in the CR males, suggesting they were at lower risk of heart disease, diabetes and other diseases of aging. Only the males on CR had somewhat lower triglyceride levels, another indicator of diminished heart risk. Males but not females on CR in the late-onset group also appeared to have experienced significantly less oxidative stress than controls; that indicates the males’ tissues were less injured by destructive molecules called free radicals, an ongoing form of molecular damage that many scientists believe is a key contributor to aging. This overall greater benefit on markers of health in males versus females may be another sign that there was something unusual about the genotypes or experimental conditions in this study. In contrast, in a landmark 2009 study showing that the drug rapamycin extends lifespan in mice in a way reminiscent of calorie restriction, females’ maximum lifespans were extended by 14%, while that of males was extended by 9%.
–Telling details related to CR’s effects on disease risks also got short shrift. For example, there were zero cases of cancer among monkeys put on CR at younger ages in the NIA study. (They were first put on CR between ages 1 and 14.) In contrast, in five of six cases of cancer among monkeys put on the control diets at younger ages, tumors were deemed to be the cause of death. Thus, as reported in many previous calorie restriction studies in mammals, CR from early in life potently reduced the risk of tumors in the NIA study. And there was a plainly visible trend toward later onset of five major diseases of aging in the young-onset CR group (cancer, diabetes, arthritis, diverticulosis, and cardiovascular disease) that narrowly missed qualifying as a statistically significant result—the P value for this difference was 0.06. (P values of 0.05 or less are considered statistically significant.) In sum, the NIA study suggested that CR improved late-life health in the monkeys, but the effect was modest and gender-specific.
–In a photograph of two 27-year-old monkeys from the NIA study that appeared in Nature, one on CR and one on the control diet, the CR animal looks a lot younger than its peer: The control monkey shows manifest signs of facial skin sagging and a hunched-back look compared to the svelte CR monkey. Interestingly, a similarly striking cosmetic difference was manifest in the Wisconsin study on CR in this species. Unfortunately, neither study provided data on markers of skin aging and other factors related to the cosmetic effects of aging.
The NIA study’s monkeys were descended from lines that came from China and India, while the conflicting Wisconsin study on CR in rhesus monkeys used animals from India alone. Thus, there may well have been significant genetic differences between the animals used in the studies.
The two studies’ dietary regimens were also quite different in several respects. Sucrose made up 28.5% of the Wisconsin diet, but only 3.9% of the NIA diet. The Wisconsin control monkeys were allowed to eat somewhat more than the NIA controls. Protein in the NIA diet came from wheat, corn, soybean, fish and alfalfa meal, while it came only from lactalbumin in the Wisconsin study. The NIA diet also included antioxidants and omega-3 fatty acids that weren’t included in the Wisconsin diet. And the control NIA animals were “supersupplemented” with vitamins and minerals compared with the study’s animals on CR, according to the Nature report; in contrast, the controls in the Wisconsin study didn’t receive extra vitamins and minerals. All these dietary factors potentially gave a boost to the NIA controls’ health as they aged, which might have contributed to the fact that they were about as healthy and long-lived as the monkeys on CR in the study.
Finally, it’s important to note that the NIA study was reported before its results on CR’s effect on maximum lifespan are available. This matters because extension of maximum lifespan is a much better indicator of an anti-aging effect than is extension of average or median lifespan—the latter are often affected by factors unrelated to aging, such as fatal infections early in life. And past studies indicate that it is entirely possible for CR to exert anti-aging effects, as measured by maximum lifespan and mortality curves, while having no effect on average or median lifespan. In a 2006 study in mice descended from wild mice captured in Idaho, for example, CR had no significant effect on average lifespan yet greatly lowered the risk of late-life cancer and increased maximum lifespan by 14%. The study suggested that in such mice, CR increased early-life mortality for some reason but exerted an anti-aging effect in mice that survived the early period of risk.
In sum, the NIA study is important because it underscored CR’s context-specific effect and shed some light on the particular conditions that tend to support calorie restriction’s anti-aging effect in primates—not because this single study overturned the general pattern that has been observed in over 75 years of studies in mammals on CR.