But the standard picture of one-way cognitive decline after about age 25 is way too simple, according to psychologists who study brain aging. In fact, their work suggests that cognitive development actually continues through middle age, and even beyond. The gist of this later development was nicely captured by the great Polish-American pianist Arthur Rubenstein, who continued to perform until he was pushing 90 (he died at 95): When asked at 80 how he managed to continue giving such good concerts, he explained that he relied on three strategems–he played fewer pieces, he practiced the pieces more often, and he used dramatically contrasting tempi to make it appear that he could play the piano faster than he actually could.

Psychologists posit that such compensatory adjustments reflect a potent capacity for “adaptive self-plasticity” built into the human genome. As we age, this capacity lets us evolve our software, so to speak, to help compensate for our inevitable loss of hardware speed and data-handling capacity. As a result, mental aging tends to bring both gains and losses. Over the past two decades, the researchers have focused on elucidating the gains, and their findings have exploded the idea that mental aging is no more than a story of decay.

For instance, they’ve shown that specialized knowledge, unlike the mental speed and accuracy of youth, can be retained through old age if used fairly often and not impaired by brain diseases. In fact, a 1999 study of people who regularly work crossword puzzles showed that the highest average level of performance on them was achieved by people in their 60s and 70s.

Another compensatory strength that comes to the fore as we age is emotional intelligence, the ability to understand the causes of one’s own and others’ feelings. We also get better at regulating our emotions. These emotion-related pluses are often more important in real-life situations than the ability to quickly deal with a lot of information. (The latter ability, by the way, is relatively easy to measure with simple tests, which is a major reason its age-related decline long dominated views on mental aging.) These pluses also underlie the “paradox of aging,” the fact that most people are happier during their later years than at any other time of their lives. Surveys show that stress and anger steadily decline after one’s 20s, that worry levels tend to fall off around age 50, and that what psychologists call global well-being (the overall appraisal of how one is doing in life) tends to slowly decline until one’s early 50s and then gradually rise–by their mid-60s, most people report significantly higher levels of well-being than they did in their 20s. (Self-reported sadness levels, though, remain nearly constant throughout life.)

Older adults also use their emotion-regulating power to deal with interpersonal tensions more effectively than younger ones do—one reason they experience less stress. In a clever study highlighting a related compensatory plus of aging, researchers asked young (aged 20-30) and older (60 to 75) adults to perform a simple memory task after watching a particularly yucky film clip. (It depicted a woman eating horse rectum in order to win money.) The young group’s performance on the memory task dropped sharply soon after they viewed the clip–it appeared they had to devote a great deal of their mental energy to suppressing their disgust in order to focus on the task at hand. Meanwhile, the older adults were able to improve their performance soon after watching the clip–it wasn’t all that hard for them to detach themselves from their negative emotions.

In another recent study titled “Don’t Look Back in Anger,” researchers asked young and old adults to play a computerized game of risk in which they opened a sequence of boxes, each of which contained either a point gain or a devil icon–hitting Satan wiped out all the gains in that round. At any point, they could either risk opening the next box in the sequence, or they could stop and add their gains from boxes opened at that point to their grand total. But if they chose to stop, they were shown what was in the unopened boxes, confronting them with missed chances for gains. Here’s what happened: The young adults tended to take more risks after viewing missed chances in the previous trial, a strategy that was irrational since the devil’s position in one trial said nothing about where it would be in the next–it seemed they were moved by anger and regret to take extra chances. In contrast, the older adults didn’t change their risk-taking based on missed chances–they tended to play with rational detachment.

(This study reminded me that one of the most spectacular examples of disastrous risk-taking in recent years involved a 20-something trader at Switzerland’s UBS investment bank who managed to blow away $2.3 billion in a series of reckless bets that went ever more wrong. Then, suddenly, I felt compelled to check the ages of the people managing the mutual funds in my IRA.)

The Piaget of later-life cognitive development is psychologist Laura Carstensen, founding director of Stanford University’s Center on Longevity. About 20 years ago she and colleagues began rethinking the idea that inexorable dwindling is the dominant theme of later life when examining how people’s social networks contract as they age. Authorities on aging had long viewed this contraction as part of the general decline of aging–the result of worsening health, loss of mental capacity, decreased mobility, increasing detachment from external events. But Carstensen showed that the contraction tends to start in early adulthood and thus doesn’t result from cognitive loss. Moreover, she found that social networks tend to include comparable numbers of very close relationships throughout adulthood despite getting smaller. What really happens, she concluded, is that we “proactively prune” our social networks as we age in order to increasingly focus on fewer but emotionally significant social partners.

In general, “socioemotional selectivity” is the essence of later cognitive development, she theorizes. Early in life, when all things are possible (or at least seem to be), it makes sense to cast our nets wide, fairly indiscriminately seeking new relationships and novel experiences in order to gain resources to realize future aspirations–even if the experiences are stressful. But as we age, maximizing emotional meaning begins to take precedence, and around midlife it appears that most of us become increasingly motivated to make the most of our remaining time and thus put a high priority on quality of life.

In short, as we age we wisely draw on our great plasticity to optimize our emotional climates: “Good times are cherished, and there is greater recognition that bad times will pass,” she wrote in A Long Bright Future, a 2009 book based on her findings about the aging mind. “People are more likely to forgive when time horizons are limited. Even the very experience of emotion changes with age; feelings grow richer and more complex…One of my favorite findings about long-term marriages is that even unhappily married couples report that, after many years together, they are happier than they used to be. It’s actually the relatively early years of marriage…that take the biggest toll on marital contentment.”

Carstensen and other “life-span” psychologists are careful not to romanticize old age, noting that their upbeat findings often don’t apply to those in poor health or living in poverty. Further, they point out, the happy days between about 60 and 80 tend to give way to unhappy days for more and more people after 80 as the limits of adaptability are reached. And dementia represents a huge problem as more of us live longer.

Still, the fact that researchers have given detailed substance to the idea that we become happier and, in ways that really matter, smarter as we age can’t help but give older language learners some solace as they struggle with their word lists.

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. 

How do we reconcile such adverse effects with the drug’s unprecedented ability to boost healthy aging and longevity, at least in mice?

Some telling insights on this burning issue were recently published in two reports on rapamycin’s effect on insulin and blood sugar: a mouse study that revealed a probable mechanism behind the effect and a theory paper suggesting that the purported diabetes risk has been overblown.

The two papers make very interesting reading for those following the anti-aging quest—if rapamycin, or drugs like it (generically known as mTOR inhibitors), work in people as they do in mice, taking them as preventive medicines in midlife should delay virtually every bodily downside of aging, from senior moments and wrinkles to Alzheimer’s and cancer. That would buy us more quality time than any other foreseeable medical advance. But this promise may be only a mirage if mTOR inhibitors pose more risks than benefits.

I’m hopeful about mTOR inhibitors’ anti-aging promise despite rapamycin’s side effects. (But I have to add that little is known at this point about such drugs’ anti-aging potential in people, and in my view it would be premature to try personal experiments with them as aging retardants.) For one thing, the troubling data on rapamycin’s side effects have come mainly from studies in which sizable doses were taken by sickly people, many of whom were on potent immunosuppressants such as cyclosporin (chiefly organ transplant patients). These data aren’t necessarily indicative of rapamycin’s side effects when taken in smallish amounts by healthy adults as a broad-spectrum reducer of degenerative disease risks (which is one way to describe an anti-aging drug). Most, if not all, of rapamycin’s side effects are dose-dependent—smaller doses pose less risk. Thus, it seems possible that a dosing regimen could be found that confers preventive gains with little risk. One expert on mTOR and aging, Mikhail Blagosklonny at Roswell Park Cancer Institute in Buffalo, N.Y., has proposed that intermittent doses of rapamycin might do the trick. Not coincidentally, Blagosklonny authored the recent theory paper downplaying the drug’s reported diabetes risk.

Another reason for hope is that there’s considerable evidence that mTOR inhibitors’ power to delay diseases of aging in mice is indicative of similar benefits in humans. For instance, such drugs are FDA-approved to ward off certain cancers, several rodent studies suggest rapamycin can lower the risk of Alzheimer’s disease, and a number of rapamycin’s key metabolic effects in both people and animals closely resemble those of calorie restriction, which is known to slow aging in diverse species. These data aren’t surprising: The mTOR enzyme inhibited by rapamycin and its ilk lies at the heart of an evolutionarily ancient metabolic pathway that governs cell growth and other basic functions. Thus, it’s probable that the pathway’s molecular components, and what they do, are quite similar in rodents and people.

One indication of the similarity is the fact that rapamycin induces insulin resistance and impairs glucose tolerance in both rodents and humans. (Insulin, a hormone released into the bloodstream by the pancreas when we eat, causes cells in the liver, muscles and other tissues to take up sugar from the blood; insulin resistance sets in when cells’ sensitivity to the hormone’s signal wanes, which can make for damagingly high blood sugar and, eventually, full-blown diabetes.) The first of the two papers mentioned above, by researchers affiliated with MIT and the University of Pennsylvania, revealed molecular details of this effect. The researchers’ mouse study showed that rapamycin inhibits two protein “complexes” in mammals, called mTORC1 and mTORC2, that have very different effects on longevity and insulin: The drug’s suppression of mTORC1 appears largely responsible for its calorie-restriction-like boosting of healthy lifespan, while its suppression of mTORC2 reduces insulin sensitivity. The scientists concluded that drugs targeting mTORC1 alone may slow aging without blood-sugar discombobulation.

But Blagosklonny’s theory paper argues that such narrow-acting mTOR inhibitors may be superfluous. His case is based partly on the fact that, paradoxically, starvation induces insulin resistance and a diabetes-like condition. This effect is pretty shocking because type 2 diabetes has long been associated with overly rich diets and obesity.

First described in the 19th century, starvation diabetes occurs when the liver becomes resistant to insulin after food intake is cut off. As Blagosklonny notes, such resistance makes sense because the liver is called on during starvation to break down proteins and fats in order to provide fuel for sugar-hungry neurons and other cells. Insulin blocks this fuel-switching mechanism (sugar usually comes from ingested carbohydrates). Thus, the liver must dial back its response to the hormone’s signal in order to produce emergency fuel from non-carbohydrate reserves in the body, as well as to prevent itself from needlessly absorbing scarce glucose from the blood, potentially causing fatal hypoglycemia (very low blood sugar). This form of insulin resistance is accompanied by a drastic reduction in mTOR activity—mTOR promotes cell growth in response to nutrient intake, and it’s activity falls off when food intake drops.

In contrast, rich modern diets cause insulin resistance via a very different mechanism: They chronically overstimulate the mTOR pathway, which evolution has designed to turn down insulin sensitivity when cells have taken up adequate fuel.

Highlighting these completely opposite mechanisms (with regard to mTOR), Blagosklonny proposes that low-mTOR starvation diabetes “only superficially” resembles mTOR-revved-up type 2 diabetes and, in fact, the former is benevolent—a view contrary to the conventional wisdom that diabetes is always pathological. Supporting his idea, a 2010 study of people who had practiced stringent calorie restriction for an average of seven years showed that they exhibited “diabetic-like” glucose intolerance (perhaps a sign of incipient starvation diabetes) while also manifesting many signs of extraordinarily good health, such as low levels of inflammation-promoting molecules linked to many diseases of aging. Further support comes from studies showing that certain mutations that disrupt insulin signaling in mice—which induces a condition resembling profound insulin resistance—can extend the animals’ lifespans.

In sum, writes Blagosklonny, insulin resistance can be good or bad—it’s bad when mTOR is amped up by overeating, and good when mTOR is inhibited by calorie restriction or by taking drugs like rapamycin. Such context-dependent assessments are common in biomedicine—for instance, weight loss due to calorie restriction promotes healthy aging, but it’s a bad thing when caused by terminal cancer. The bottom line, he concludes, is that the diabetes-like side effects induced by rapamycin shouldn’t be regarded as an obstacle to pursuing it as an anti-aging drug for humans.

Now all we need is a brilliant billionaire to step forward and fund the pursuit.

The hunt for such “gerontogenes” took off around 1990 when scientists discovered that mutations in certain roundworm genes could double their lifespans. A few years later, similar genes were found in mice, thanks partly to pioneering research at Jackson Laboratory led by two coauthors of the new study, Kevin Flurkey and David Harrison. The findings helped turn aging science into a hot field and raised hopes that drugs could be found that would mimic the effects of the mutations and thus slow human aging.

But the mouse gerontogenes discovered so far haven’t been very promising drug targets. They mainly work by disabling growth-regulating hormones, which despite extending lifespan typically causes dwarfism, infertility, and other problems. Indeed, says Flurkey, drugs mimicking the mutations “would probably shorten the lifespan of anyone who doesn’t live in a bubble (or at least in sterile, pathogen-free mouse colony with constant temperature and no stress).”

Moreover, it has been very hard to identify such genes. For one thing, pinning them down has required costly, arduous rodent lifespan studies that can go on for over four years.

Yuan’s study, published in the May 7 issue of the Proceedings of the National Academy of Sciences, established a shortcut to finding novel mouse gerontogenes. It was based on the theory that delayed sexual maturation is an indicator of slow aging later in life. That implies unusually slow-aging strains of mice can be identified via relatively short studies in which their age at sexual maturity is measured. (That age can be readily determined by assessing how long it takes females to reach “vaginal patency”–typically three to six weeks from birth.) With rodent strains in hand that are probably slow-aging, researchers can scan their genomes for gene variants correlated with slow development and aging.

But this strategy will only work if an individual’s slow sexual maturation really does make for slow aging and longer lifespan. Evolutionary theory says it should, and studies with animals on near-starvation diets have shown that calorie-restriction diets both delay sexual maturation and slow aging. But the Peter Pan corollary, as Harrison has dubbed it, hadn’t been rigorously tested before Yuan and colleagues showed in the new study that sexual-maturation rates are indeed correlated with longevity in different strains of mice.

The Jackson team also applied the technique to identify a novel gene, called Nrip1, affecting the rate of aging, at least in mice. Females with disabled Nrip1 genes are slow to mature and, according to preliminary evidence, are also strikingly long-lived. Intriguingly, Nrip1-disabled mice were found to resemble long-lived, calorie-restricted ones in key respects. For instance, they have unusually low levels of a growth-promoting hormone, IGF-1, that has previously been shown to be a key regulator of the rate of aging in mice and other species, possibly including people. And Nrip1 is known to help control formation of new mitochondria, cells’ power plants, whose running down as we age is thought to be a major contributor to the body-wide deterioration of aging.

(Interestingly, a recent, high-profile mouse study led by Harvard’s David Sinclair has shown that resveratrol, the famous red-wine ingredient, induces health benefits like those of calorie restriction largely by improving mitochondrial function.)

Besides facilitating the quest for anti-aging genes and drugs, the Jackson Lab study points to a troubling hypothesis: that childhood obesity, which is correlated with early puberty in girls, works like the Peter Pan corollary in reverse. That is, if slow development goes with slow aging, it seems quite possible that rapid early development, which is abetted by rich diets that bring on obesity, may lead to a physiological state closely resembling accelerated aging. In short, the obesity epidemic may in effect be prematurely aging a broad swathe of the population, which has dire implications for our society’s future burden of disease, healthcare costs, and the economy.

To be sure, this Peter Pan-in-Reverse hypothesis is speculative. But it is consistent with a lot of data on the tie between early puberty, obesity and premature onset of aging-associated diseases—not to mention the fact that the ageless Peter Pan, as far as I know, has never been portrayed as overweight. If only we could assess the functionality of his Nrip1 gene.

First, it has never been clear how much progerias can tell us about normal aging. Further, it’s not even clear which life-shortening syndromes to anoint as forms progeria, which implies that they have something to do with aging—there are a myriad degenerative diseases that shorten life and cause forms of bodily decay reminiscent of aging’s toll, and it’s a judgment call, sometimes rashly made, to label one of them a form of accelerated aging. Besides, no one knows whether 10% or 90% of the zillion forms of deterioration caused by aging, or something in between, must be present in a purported form of progeria in order for it to tell us truly interesting things about aging. As a general rule, I tend to think that progerias that kill very early in life, as does the one investigated in the Pittsburgh study (it’s called XFE progeroid syndrome, by the way, and it kills mice with a few weeks of birth), are usually less like normal aging than ones that work slower. Thus, I didn’t find the Pittsburgh study all that interesting at first glance—it seemed to be about a possible treatment for a rare congenital disease, not a study on aging.

But I found it more interesting when I took a closer look. The Pittsburgh group has conducted a number of studies over the past few years that suggest XFE progeroid syndrome does indeed resemble something like normal aging at warp speed. Like a number of other purported accelerated-aging syndromes, it hinders the repair of damaged DNA, and there’s much evidence that nicked, bent or otherwise uglified DNA is one of the main drivers of aging. (But determining whether DNA damage is aging’s root cause is almost as hard as deciding whether chickens cause eggs, or vice versa.) XFE progeria broadly induces degenerative changes across organs, including neurodegeneration, early deterioration of vertebral discs, and liver dysfunction. It also engenders patterns of gene activity early in a mouse’s life resembling those that occur late in life in normally aging mice.

The injected cells that extended the lifespans of the progeroid mice in the most recent study—known as MDSPCs, or muscle-derived stem/progenitor cells— were previously shown to be capable of stimulating the regeneration of bone, skeletal and cardiac muscles. The new study is particularly interesting because it suggests that the injected cells secreted factors, currently unknown, that braked degenerative changes in the fast-aging mice. That has raised hopes that these mysterious molecules might be isolated and used to slow such tissue deterioration in normal aging, perhaps by perking up various flagging organs’ tissue-repairing stem cells.

But there are still a lot of reasons to doubt that this research will lead to youth preservatives. For one thing, a few years ago researchers identified the first human case of a genetic defect similar to the one in mice with XFE progeria: it struck an infant that was born with dire defects, including severe head, hand and foot deformities, and led to the baby’s death at 14 months of age—the syndrome looked more like a genetic disease that profoundly messes up development than aging.

Further, great caution is warranted about any intervention that purports to increase cells’ regenerative powers because such treatments can increase the risk of cancer—it’s extremely tricky to juice up normal cell growth without also juicing up the out-of-control growth of tumor cells. This risk is virtually impossible to assess in animals that die at less than a month of age, as did the Pittsburgh mice—cancer generally takes more time to develop than that. Still, I think this story could get a lot more interesting in the near future as researchers further investigate this progeroid syndrome—including a slower-acting, milder form of it that can be induced in mice—and the young-cell-secreted agents that mitigate it.

Led by Wen-Bin Chiou at National Sun Yat-Sen University, the researchers gave daily placebos for a week to 82 adults (45 women, 37 men, average age 31). They told half of the group that they were taking multivitamins, and at the end of the week administered surveys on the subjects’ health-related inclinations. The results: Those who thought they were taking vitamins reported a 44% higher tendency to partake in risky activities (examples included casual sex, sunbathing, and binge drinking), and a 61% higher preference for all-you-can-eat buffets over healthy meals, compared with those who knew they were taking placebos. The “multivitamin” group also reported exercising 14% less. The researchers concluded that multivitamin takers may experience an “illusory invulnerability” contributing to all kinds of risky behaviors.

In a related study, Chiou and colleagues gave placebos to a group of smokers, some of whom were led to believe that they were getting multivitamins or another dietary supplement perceived as protecting health, such as vitamin C. As expected, those who thought they were taking dietary supplements smoked more cigarettes. And the more positive that smokers felt about the presumed benefits of the fake supplements, the more they smoked. I find this study particularly ironic because taking beta-carotene and vitamin A can substantially increase a smoker’s risk of getting lung cancer.

One reason all this is interesting is that a few years ago prominent biochemist Bruce N. Ames, at the Children’s Hospital of Oakland Research Institute, proposed an intriguing theory about aging and vitamins that suggests taking multivitamins might well be a good thing as a general rule. Briefly, his “triage hypothesis” holds that evolution has geared our bodies to selectively allocate scarce micronutrients (essential vitamins and minerals) to support metabolic functions that help insure near-term survival, which means that short micronutrient rations are given to less-urgent metabolic processes when diets aren’t well-balanced—a dietary plight that was likely often the case for our ancestors, and that Ames argues is probably also the case for many people today who consume a lot of junk food. Unfortunately, the short-rationed metabolic processes tend to be the very ones that help protect us from the relatively slow-acting damage that probably underlies aging, such as repairing frayed DNA (damaged DNA can lead to cancer and many other diseases of aging).

Like most hypotheses related to nutrition, this one is controversial and hard to prove. But it is consistent with the generally accepted evolutionary theory of aging, which holds that natural selection works to keep us healthy and vibrant when we’re young, but effectively loses interest in us as we grow older, allowing us to get trashed by things such as free-radical damage to DNA and other biodegrading insults—as evolutionary biologist George Williams observed in 1957, whenever there’s a tradeoff that evolution has to make affecting health and survival, it invariably favors the choice that promotes vibrancy early in life, even if that has dire delayed effects that play out in later life. Ames’s theory can be seen as an offshoot of this “antagonistic pleiotropy” principle.

So does it make sense to take a daily multivitamin after all? Ironically, it would seem the answer is most likely to be yes for those who tend to eat junk and make other poor lifestyle choices, and thus who would also be the kind of people most likely to suffer ill effects caused by the illusory invulnerability that goes with popping vitamins. As for me personally, I’ve decided to pop a multivitamin on the relatively rare days when I remember to do so, and on those days to take special pains to steer clear of orgies, sunburns, binge drinking, and all-you-can-eat restaurants.

Recent placebo-controlled clinical trials with resveratrol, however, suggest that much smaller doses—maybe a tenth as much as suggested by the Times‘ story—can have significant cardiac benefits. These smaller doses are still too large to get from drinking wine—you’d need to take resveratrol pills to equal them. But evidence is plainly growing that a rethink is in order.

Before we get into rethinking, you should note that a recently published “Systematic Review and Recommendations on the Use of Resveratrol” by 21 scientists concluded that while the animal data on the compound are “promising,” it’s too early to recommend that people take resveratrol supplements. Despite the fact that there are now well over 4,000 published research papers concerning resveratrol, that’s not surprising. Until large, rigorous clinical trials with it are conducted, little can be said with confidence about its effects in people. Unfortunately, it’s likely that we’ll all be long-goners before such trials are conducted. The reason: Resveratrol supplements are low-margin products that don’t generate enough profits for their makers to support funding of large clinical trials, which could easily cost hundreds of millions of dollars. Not surprisingly, the recent trials were small and brief.

Still, the picture has become a little clearer since the 21 scientists duly weighed in as agnostics on resveratrol. As I mentioned in my recent blog on sirtuin news for mammals, the latest resveratrol studies have indicated that chronic daily doses on the order of 100 to 200 milligrams induce metabolic changes that presumably can improve cardiovascular health, including lowered systolic blood pressure. By comparison, the human-equivalent dose mentioned in the 2006 New York Times story on the tubby mice was 1,344 milligrams—about ten times as much. Some resveratrol makers encourage people to pop such megadoses by hawking pills containing 1,000 or more milligrams. That’s a lot: While resveratrol has been deemed safe at daily doses up to 5,000 milligrams in trials with healthy volunteers, transient diarrhea and nausea have reportedly occurred in some people at doses over 1,000 milligrams a day—see here for more on this.

But why would the surprisingly small doses produce readily measured benefits in people? After all, various studies have found that resveratrol is very quickly metabolized away—peak blood levels occur only about 30 minutes after doses are ingested, followed by rapid disappearance of the compound from the bloodstream.

One possibility is that resveratrol’s “metabolites”—relatively long-lasting compounds produced as the body breaks down and eliminates resveratrol—have resveratrol-like effects. A few studies (here’s a recent one) have suggested that these metabolites do have such effects on various enzymes. In addition, some of the metabolites may be slowly turned back into resveratrol in the liver. But it’s still not clear whether the metabolites have significant effects.

Another take on the dosage issue was offered in 2007 by Wisconsin researchers who spotted a glaring mistake in media reports on the topic. As they observed, medical writers (including me, by the way) naively assumed that it made sense to calculate a human-equivalent dose (HED) from the mouse data by assuming that people are, metabolically speaking, the same as heavy mice. In one of the 2006 studies, mice were given 22.4 milligrams of resveratrol per kilogram of body weight; thus we reporters presumed that the HED for a 60-kilogram person (that’s about 132 pounds ) would be 60 times 22.4 milligrams, or 1,344 milligrams—the dose specified in the New York Times piece. But that’s not how the pros do it, the Wisconsin researchers pointed out. Drug developers calculate HEDs based on body surface area, not weight. This method, officially endorsed by the FDA, goes back to the late 1800s, when it was discovered that mammals’ oxygen utilization, calorie expenditure and blood volume are much more closely correlated with body surface area than with weight. Based on the surface-area method, the human equivalent of the resveratrol dose given to the fat mice is a mere 109 milligrams for a 60-kilogram person, not 1,344. Whoops.

As it happens, some of the most interesting cardiovascular-related animal studies on resveratrol have been conducted not in mice, but in special strains of rats prone to high blood pressure. In 9 of 11 such studies, resveratrol doses were found to reduce the rodents’ elevated blood pressure, according to the systematic review cited earlier. In these studies, rats got daily doses of 10 milligrams per kilogram of body weight or higher. Based on the surface-area method, the human equivalent of a 10-milligram rat dose per kilogram of body weight would be 97 milligrams for a 60-kilogram person.

Importantly, these remarkably consistent rat studies fit nicely with the recent human clinical data on resveratrol, as well as with a well-established mechanism that may partly explain the compound’s cardiovascular benefits: Since the early 2000s researchers have known that resveratrol stimulates release of a compound called nitric oxide, or NO, from “endothelial” cells that line the inside walls of arteries. Since NO causes arteries to dilate, this probably enables resveratrol to lower blood pressure. In 2007, University of Pittsburgh researchers discovered that resveratrol likely boosts NO, at least in part, by revving up a sirtuin enzyme called SIRT1. Earlier this year, a team at the University of Colorado shed further light on the topic by showing that production of SIRT1 by endothelial cells falls dramatically with age in both mice and humans, and that aging arteries get stiffer and less elastic in tandem with this change, impairing their ability to readily dilate. (Reduced artery elasticity is closely correlated with heightened risk of atherosclerosis and heart disease.) All these parallel findings suggest that resveratrol may retard key aspects of artery aging by stimulating SIRT1.

In sum, a heartening number of mostly consistent studies in cell culture, rodents and humans indicate that resveratrol helps promote cardiovascular health, at least in part by stimulating SIRT1. The studies still fall short of what it would take to convince medical authorities to recommend that people at elevated risk of heart disease try resveratrol. But I wonder how many of those experts are now quietly taking the stuff themselves—at modest doses, of course.

Partridge, along with editors of Science, apparently see the sirtuin story as an overfilled balloon begging to be popped. Joining in the fun, Nature‘s editors recently ran a headline—”Don’t write off sirtuins”—implying that they’re now in danger of being placed in the same category as a deadbeat’s IOU. But thanks to all the gleeful popping, we’re faced with a strange situation: The studies in yeast, worms and flies have totally upstaged a large, growing body of encouraging findings on sirtuins and resveratrol in mammals, including several small but revealing human clinical studies that recently appeared with little or no media notice. This situation is a first as far as I know when it comes to coverage of an important biomedical topic.

Don’t get me wrong: The studies in lower organisms have shed intriguing light on sirtuins and helped dispel simplistic views on how they work. But to my admittedly mammalian eyes, the recent heavy emphasis on them leaves something to be desired. If you happen to be warm-blooded, what follows are a few intriguing findings on sirtuins that you may have missed while reading about how the story on them has unraveled. (If you’re a fly or worm, just skip it.)

–In an Australian study of 19 overweight and obese people with borderline high blood pressure, taking single doses of dietary supplements containing 30 to 270 milligrams of resveratrol (the brand name was resVida) was found to yield a statistically significant improvement in a measure of cardiovascular health called flow-mediated dilatation of the brachial artery, or FMD, one hour after the doses were taken. (FMD is is a widely-used measure to assess heart-disease risk.) Importantly, the researchers showed that the higher the resveratrol dose, the greater the improvement—such dose-dependency suggested that the observed improvements weren’t flukes, and that they were due to the resveratrol doses. The study was funded by resVida’s maker, Switzerland’s DSM Nutritional Products.

–A double-blind, randomized study of 19 patients with type 2 diabetes showed that taking 10 milligrams a day of resveratrol supplements for four weeks induced a statistically significant drop in blood glucose after meals and a lessening of other signs of insulin resistance (the hallmark symptom of diabetes). That daily dose was not much more than moderate wine drinkers get—some red wines contain 1 to 2 milligrams per glass. (The idea that a person would have to knock back whole cases of wine to get significant health benefits from resveratrol, suggested by 2006 mouse studies in which the animals were given huge doses, now appears to have been wrong.) The Hungarian researchers who led the study at University of Pécs suggested that resveratrol’s ability to reduce oxidative stress (the kind of damage caused by free radicals) might underlie the benefits they saw.

–A double-blind, randomized trial of 11 obese males who took 150-milligram resveratrol supplements for 30 days (resVida, whose maker helped to fund the study) showed that men experienced a number beneficial metabolic changes resembling those seen in mice on much higher doses. While “modest,” the changes—including lower systolic blood pressure, signs of reduced body-wide inflammation, and enhanced energy metabolism leading to reduced fat deposits—suggested that surprisingly small doses of resveratrol can rapidly induce beneficial effects resembling those of calorie restriction or endurance training. The study also presented evidence that the metabolic changes were mediated by an enzyme called AMPK, which in turn revved up SIRT1, a sirtuin that many studies have implicated in mammalian aging and calorie restriction.

This latter study made the cover of Cell Metabolism, a prominent journal. But it garnered little media attention, despite the fact that its blood-pressure finding alone was arguably quite important. Briefly, the researchers showed that taking the smallish doses of resveratrol supplements for a month yielded a statistically significant reduction in systolic blood pressure (the P value was 0.006, indicative of a robust result despite the small number of subjects)—it dropped from 130.5 on placebo to 124.7 on resveratrol (we’re talking millimeters of mercury, of course). The finding was consistent with a growing body of evidence that boosting SIRT1 can lower blood pressure—see here for a recent example. The 5.8 mm reduction in systolic pressure may sound small. But it has become increasingly clear in the cardiac literature that even small reductions in blood pressure can have major effects on disease risks as people age. As an important 2006 study showed, adults with “high normal” blood pressure, defined as having systolic readings between 130 and 139, have more than twice the risk of cardiovascular disease as people with readings below 120.

With the exception of the Dutch study, the recent human studies on resveratrol didn’t shed much light on whether the chemical works by activating SIRT1. That issue is hotly debated, with sirtuin skeptics asserting that resveratrol’s calorie-restriction-like effects have nothing to do with SIRT1, while others, most notably David Sinclair at the Harvard Medical School, contending that its effects are largely channeled through SIRT1. Perhaps of most interest to warm-blooded readers, a number of mammalian studies on resveratrol’s effects have suggested SIRT1 is a key channel through which the substance can improve cardiovascular health. (For some examples, see here, here and here.)

A recently reported mouse study at the National Institute on Aging also lent support to the idea that amping up SIRT1 in mammals on overly rich diets can help avert the diets’ hurtful effects in a way that resembles what calorie restriction (CR) does. (It should be noted, though, that resveratrol has failed to extend the lifespans of normally-fed mice in earlier studies, suggesting that, at most, it only partly mimics CR’s effects in mammals.) The study, overseen by the institute’s Rafael de Cabo, looked at the effects of SRT1720, a drug developed by Sirtris Pharmaceuticals, a biotech cofounded by Sinclair and now a part of GlaxoSmithKline, to stimulate SIRT1 more potently than resveratrol does.

SRT1720 may ring a bell—sirtuin skeptics are fond of trotting out a Pfizer study last year suggesting that the drug doesn’t really stimulate SIRT1 and, worse, is actually toxic to mice. The toxicity finding was based on the administration of SRT1720 to 8 mice for 18 days. In the national institute’s study, an equivalent daily dose was given to over 100 mice for more than 80 weeks while they given fattening food; not only did the animals show no signs of toxicity, but they lived, on average, up to 44% longer than similarly fed mice that didn’t get the drug—not surprising, given the study’s other data indicating that the drug fended off deleterious effects of their overly rich diets. Indeed, the reduction of liver fat in the SRT1720-treated mice was so pronounced that it was “apparent even to the naked eye” in tissue samples, their increased longevity (of both maximum and mean lifespan) was dose-dependent (more resveratrol yielded bigger gains), the drug suppressed inflammation-associated changes in the rodents’ livers and hearts, it improved their insulin sensitivity, and it caused gene-activity changes resembling those induced by both resveratrol and calorie restriction. Call me a prejudiced Eutherian if you like, but I find this rigorous, long-term mouse study, which is consistent with several others on SRT1720, more compelling than Pfizer team’s brief look at the drug.

While the national institute’s study didn’t conclusively show that SRT1720 acts via SIRT1, the researchers found that telltale changes induced by the drug in liver-cell mitochondria, tiny power plants in cells, didn’t occur in mice with disabled SIRT1 genes—evidence that the sirtuin enzyme is a major conduit of the drug’s action. Similarly, a number of other studies involving bioengineered mice with SIRT1-disabled and SIRT1-enhanced genes have suggested that boosting SIRT1 helps ward off diabetes and other diseases brought on by aging and obesity. A good review on these data can be found here.

All these mammalian results on sirtuins, resveratrol and sirtuin-targeting drugs don’t prove that the earlier, over-the-top excitement about them was warranted. Perhaps the strongest conclusion that an unbiased observer could draw at this point from all the data on sirtuins is that their activity depends very much on the context in which it is observed. Importantly, however, the context of greatest interest for most of us aging mammals is aging mammals, where boosting sirtuin activity appears to do really nice things in certain organ systems. And if I were an obese mammal with hypertension, I’d be sorely tempted at this point to try taking modest daily doses of a resveratrol supplement for a month to see whether it brings down my blood pressure. While I wouldn’t expect such an experiment to make me live a lot longer, I think I could justifiably entertain the hope that it just might help me age more gracefully.