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.

Not surprisingly, the multivitamin finding got a lot of media attention—surveys show that at least half of U.S. adults regularly take vitamin supplements, and, of those, about 75% take multivitamins—and so it’s likely that millions of people are now worried that they may be at risk of early death from some sort of mysterious biochemical imbalance induced by doing what once seemed a no-brainer good thing. But the purported risk may not be real. In fact, my guess is that it’s not.

For one thing, the multivitamin data didn’t prove cause and effect. Rather, it merely showed an association between taking multivitamins and a slightly elevated mortality risk. (To establish cause and effect, you minimally need multiple, well-controlled studies showing a consistent pattern of harm across different groups of people exposed to a particular risk factor.) What might lie behind the association besides the unlikely possibility that multivitamins somehow abet mortal sickness? (I say unlikely because multivitamins generally contain only modest amounts of vitamins geared to meet well-established minimum daily requirements—they don’t deliver megadoses, as single-vitamin supplements often do, that are way beyond what you’d get from eating a balanced diet.)

Here’s what I think is really going on: After taking a daily multivitamin, people feel that they’ve at least partly shielded themselves from the effects of unhealthy lifestyles, making them a little less likely than they might otherwise be to skip the fries, to dispense with the daily soda or three, or to replace some of their TV time with exercising. Thus, my guess is that the slightly higher risk of death linked to multivitamins reflects a slightly elevated risk of being relaxed about doing all the wrong things, including health risks that multivitamins do nothing to offset, even if they do help make up for not eating enough fruits and veggies. Indeed, America’s obesity epidemic suggests that people generally aren’t all that worried about what their unhealthy lifestyles are doing to them. Multivitamin sellers’ pitches, even if just reciting the facts about how essential vitamins are to health, can’t help but feed their false sense of security. And as I’ve argued here and elsewhere, our sedentary, fattening lifestyles have much higher costs than is generally recognized—when it comes to the increasingly heavy burden of disease weighing down our society, it has the budget-busting effect of prematurely aging the entire population.

In contrast to the multivitamin study, which said little to nothing about cause and effect, the one on vitamin E and prostate cancer was a randomized clinical trial that added some compelling evidence to a growing body of clinical research that strongly suggests taking large doses of antioxidant supplements, in particular vitamins E, A and beta carotene, really does increase the risk of dying by about 5%. The discovery of this risk hasn’t proved that Denham Harman’s venerable free radical theory of aging is wrong. But as explained in my book, and in a piece I wrote for Boing Boing, the idea that popping big doses of antioxidants can prevent us from rusting out like old cars exposed to too many Boston winters now seems a dangerous myth propagated by antioxidant hucksters. One reason may be that taking such doses discombobulates our well-honed inner systems to fend off free-radical damage, ironically increasing our risk of such damage. And naturally-occurring free radicals are also thought to help induce cells with precancerous DNA damage to commit suicide—a process called apoptosis—before they turn into full-fledged tumor cells. Artificially quashing the radicals with big doses of antioxidants may interfere with such altruistic self-sacrifice for the greater good, enabling precancerous cells to stick around until further DNA damage turns them into unstoppable monsters. That definitely wouldn’t make for healthy aging.

This is more than a personal health issue. As I recently wrote on the Miller-McCune website, obesity is a leading contributor to ballooning healthcare costs, and more than any other factor such costs are responsible for busting government budgets. Thus, it’s arguable that one of the main drivers of our nation’s fiscal malaise is a little-recognized phenomenon: The obesity epidemic has prematurely aged a third or more of the population by a couple of decades, presenting us with huge medical bills for a myriad “old-age” diseases that we had once expected would come due gradually with population aging over the next few decades. Indeed, you might say this issue is the hidden elephant in the room as policymakers furiously debate what to do about exploding entitlement costs and the federal deficit.

This idea that obesity is tantamount to accelerated aging makes sense in light of what’s known about calorie restriction: In general, the more calories that are cut from animals’ diets (without causing malnutrition or starvation), the longer they live in good health. This suggests that, roughly speaking, the richer the diet, the faster the aging. (I say roughly because various studies indicate that unusually thin people have higher mortality rates than normal-weight ones, which probably rules out the existence of a simple relationship between calorie intake, body-mass index and aging. On the other hand, it may be that many thin people are thin because they suffer from subtle, long-term health problems—former smokers, for example, may seem perfectly healthy in midlife but harbor subtle lung damage whose ill effects are manifested many years later in the form of wasting diseases such as chronic obstructive pulmonary disease. Thus, in many cases unusual thinness may well be an effect of subtle, underlying health problems that play out over many years to increase the risk of early death—not a cause of them.)

There’s also growing evidence that obesity engenders many of the same changes that aging does at the cellular and molecular levels. For instance, potbellies, formally called visceral fat, have a strong pro-inflammatory effect, and hundreds of studies over the past two decades have suggested that low-level, body-wide inflammation, which tends to increase with age, is a key driver of just about every major disease of aging, from Alzheimer’s to arthritis. (It appears that such inflammation even increases the risk of chronic stress and depression.)

Fascinating connections between obesity and aging have also come to light as in recent research on a gene called mTOR (mammalian target of rapamycin). Mikhail Blagosklonny, a researcher at the Roswell Park Cancer Institute in Buffalo, has elucidated these connections in a compelling new theory of aging. Briefly, the theory rests on the fact that mTOR’s main mission is to gear our cells’ growth to food intake—mTOR is activated in tandem with rising nutrient levels, giving cells a green light to grow and divide when inner resources are adequate for that; when they’re scarce, mTOR is deactivated and its pro-growth signal wanes. Here’s the key thing: Suppression of mTOR by reduced food intake also activates metabolic pathways whose combined effect both conserves energy and opposes the aging process. They include “stress-response” pathways, which help fend off cellular damage, and a cellular recycling function, called autophagy, which clears away molecular gunk that tends to build up as we age and contribute to everything from neuronal decay to wrinkles. As Blagosklonny explains, mTOR activation is essential to foster growth and development early in life. But after that, its unchecked pro-growth activity—he compares mTOR to a brakeless car barreling toward disaster as we age—fosters various forms of damaging cellular hyperactivation, leading to atherosclerosis, accumulation of fat, low-level inflammation, insulin resistance, and other pro-aging processes that culminate with the onset of cancer, heart disease, dementia, and other killer diseases. Add rich diets and sedentary lifestyles to this picture and the brakeless mTOR car speeds up and goes over the cliff faster than ever.

In an extended riff on Blagosklonny’s theory, I recently proposed in a paper in the journal Aging that the relentlessly rising prevalence of obesity is behind a trend toward increasingly rapid sexual maturation in recent decades—in effect, the aging process has been starting ever earlier as kids have gotten fatter. This phenomenon, which I speculate has roots in our species’ evolutionary past, has especially dismaying implications about our society’s oncoming tsunami of obesity-associated diseases and skyrocketing healthcare costs.

To be sure, the detailed physiological effects of obesity are probably different in some important respects from those of normal aging. In particular, it seems likely that obesity accelerates the decay of certain organs more than others, and that this organ-specific pattern of deterioration is somewhat different from the deterioration caused by aging without obesity—normal aging, for example, isn’t known as a risk factor for liver cirrhosis. But the ultimate fallout from these two, somewhat different patterns of decay is remarkably similar—as one researcher put it, when it comes to chronic diseases, being obese is roughly the same as being aged by a couple of decades.

In sum, you might say that obesity doesn’t so much speed up our journey toward late-life decrepitude as forcibly steer us onto a short-cut toward it. I can’t think of a better example of haste making waste.

I didn’t have the space in my Fortune piece to delve into the deep, fascinating question it raised—why might resilience abet graceful aging—and so I decided to take it up here. I’ll get right to the point: I think highly resilient, stress-resistant people tend to be quite literally less inflamed as they age than most of us. Let me explain.

In recent years one of the most intriguing developments in psychiatric research has been the discovery that signs of heightened body-wide inflammation are closely associated with chronic stress and depression. This has been more than a little surprising, given that stress has long been regarded as suppressing the immune system, as well as dampening inflammation (which helps rev up immune cells to fight off infections).

But the tie between revved-up inflammation and stress/depression has now been shown in numerous studies, and it can’t be dismissed as a weird anomaly. A possible explanation for the paradox is that moderate stress of limited duration does indeed suppress the immune system, perhaps as part of an evolved mechanism to free up bodily resources to flee or fight when danger threatens. But chronic stress may overactivate mechanisms whose normal function is to damp down the red-alert state after danger has passed. Eventually this compensatory overactivation may produce an effect that’s just the opposite of the one that short-lived, moderate stress does on inflammation. This is by no means the only explanation, though I think it’s the most compelling one—another idea that’s been floated is that overeating and obesity go with depression, especially in women, and obesity is well known to be pro-inflammatory.

Regardless of why the inflammation-depression connection exists, it has highly interesting implications for psychiatry and other fields of medicine. For instance, it can explain why administration of vaccines, which transiently induce inflammation, sometimes causes healthy, normal people to suddenly get depressed and anxious. Cancer patients given immune boosting drugs, which are pro-inflammatory, also sometimes get profoundly depressed. Signs of heightened inflammation are also linked to impaired sleep and fatigue in depressed patients. The connection may also explain why some depressed people tend to respond better to antidepressant drugs when the medicines are given with anti-inflammatory compounds such as aspirin, as well as data suggesting that anti-inflammatory omega-3 supplements have can have antidepressant effects. For more details on these phenomena, see this recent review.

What’s most interesting to me about the connection are its larger implications about aging. In recent years it has become abundantly clear that low-level inflammation lies at the heart of many diseases of aging, and also may be a major driver of the overall aging process that causes our risk of fatal diseases to soar as we get older. Thus, the discovery that chronic stress abets such inflammation carries implications that stretch across the entire medical literature, not just psychiatry.

All this also suggests a major reason (probably not the only one) why highly resilient people, possibly including many famous actors, may be relatively slow agers: Their upbeat temperaments may make them resistant to the pro-inflammatory effects of stress. Don’t despair, though, if you’re a gloomy Nordic type. Anti-inflammatory interventions may help those who aren’t blessed with great resilience or unusually sunny personalities—most of us, that is—age more gracefully, and perhaps more cheerfully, as well as counteract the physically damaging effects of chronic psychosocial stress. Such stress is an increasingly urgent issue as the population ages, partly because caregivers of loved ones with cancer, dementia, and other chronic diseases of aging often face heavy stress for many years of their lives—it’s often seems as if they are transferring some of their own life- and health-spans to elderly parents.

In keeping with these ideas, recent data from the fetchingly named “Heart and Soul Study” in California showed that heart-disease patients with relatively high blood levels of omega-3—which probably meant that they ate lots of fish or took fish-oil supplements—tended to have less wearing away of the telomeres in their white blood cells as they aged. Worn telomeres, which are protective end-caps on chromosomes, are a sign of cellular aging, and ground-down telomeres in white blood cells is regarded as a sign of immune-system aging, and possibly also an indicator that many other types of cells in the body are getting decrepit—scientists call such cellular decrepitude the senescent phenotype, and it’s thought to underlie everything from wrinkles to cancer.

So how to dampen chronic, low-level inflammation? I’m not recommending that you rush out and try these, but there are data suggesting that several dietary supplements, such as resveratrol (at some dose that isn’t clear) and omega-3 (at high doses of at least 2 grams a day), can have the desired effect, at least in some people. Aspirin and other anti-inflammatory medicines such as ibuprofen also deserve consideration. There’s some evidence to suggest that yoga and meditation can be anti-inflammatory too. Perhaps best of all is the anti-inflammatory effect of regular exercise and maintaining your weight in the normal range.

Will any of these help your inner Demi come forth as the years pass? I don’t know the answer, but I have to say that someday I hope one of the paparazzi takes close-up of Ms. Moore’s telomeres.

But an even more tantalizing story about the drug has quietly emerged over the past few years: Research on longevity-linked genes carried by centenarians suggests that anacetrapib and other experimental medicines in its class, called CETP inhibitors, may mimic the effects of one of them. That means people who take CETP inhibitors to lower heart risks may experience a fascinating side effect—their risks of diabetes, Alzheimer’s disease and many other diseases whose risk soars with age may be greatly lowered as well.

CETP inhibitors alone are unlikely to confer the wondrously slow rate of aging experienced by people who are still in good shape at 100, many of whom look several decades younger than they are. Only about one in 10,000 people lives to 100, and achieving such extraordinary longevity probably requires at least several anti-aging genes—centenarians have hit the genetic jackpot. And CETP-inhibiting drugs may only partly mimic the longevity-correlated CETP gene. Still, various studies suggest that CETP inhibitors may turn out to be broad-scope preventive medicines that protect not only our hearts, but also our brains and other organs as we get older. If so, they might confer unexpectedly large gains in quality time as we age—forget blockbuster status, we’re talking baby boomer manna.

The idea that CETP inhibitors might mimic an anti-aging gene sprang from centenarian studies in the early 2000s led by Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx. One of Barzilai’s first major discoveries was that his elderly subjects not only tended to have strikingly high HDL levels, but also unusually large particles of both HDL and LDL in their blood. The particle-size finding was highly intriguing, partly because it made sense. HDL, or high-density lipoprotein, transports cholesterol to the liver for disposal, and larger HDL particles probably carry more than smaller ones. Large LDL particles, which also pick up cholesterol, may be less likely than smaller ones to find their way into artery walls, which leads to the artery clogging of atherosclerosis.

In light of these initial discoveries, Barzilai’s team scanned lipoprotein-related genes in their elderly subjects and soon discovered that a remarkably large number of them carried a certain variant of the CETP gene. In keeping with their prior findings, the variant was linked to large lipoprotein particle sizes, as well as both higher HDL levels and lower CETP levels. (The fact that lowering CETP boosts HDL was discovered earlier and motivated the development of CETP inhibitors.) Adding weight to the finding, an Italian team subsequently reported a strikingly high prevalence of the same CETP variant in a different set of very old people. (It should be noted, though, that not all studies on the CETP variant have agreed with Barzilai’s findings on its broad risk-lowering effect.)

Studies by Barzilai and others have now linked the longevity-associated CETP variant to reduced risk of atherosclerosis, heart attacks, high blood pressure, diabetes, age-related cognitive decline, Alzheimer’s disease and other forms of dementia. The remarkable scope of these potential benefits suggests that the CETP variant does a lot more than protect the heart—it may broadly affect the aging process. Indeed, besides its cholesterol-transporting benefit HDL is thought to have both anti-inflammatory and antioxidant effects, and a mountain of research on aging suggests that cutting inflammation (which tends to insidiously increase with age, contributing to everything from cancer to dementia) and free-radical damage (which batters DNA and other key molecules, and is opposed by antioxidants) may help slow down our transformation from springy youths into frail seniors.

Drug companies developing CETP inhibitors (Roche also has one in the works) aren’t about to pursue them as anti-aging drugs—unfortunately, aging isn’t recognized by drug regulators as a condition warranting pharmaceutical intervention, and thus pharma companies can’t sell anti-aging medicines as lucrative prescription drugs. Nonetheless, if CETP inhibitors reach the market as cardiovascular medicines, we’ll witness a very interesting development: Millions of people will inadvertently take part in a massive experiment on the power of the novel drugs to confer something like the radical resistance to ravages of time that centenarians enjoy as a birthright.

The fact that these records have stood for over a decade is more than a little surprising. During the 20th century there were continual improvements in longevity and mile-running times. In the late 1990s it seemed the gains would continue apace—there were obviously limits to what the human body could do without bionically rebuilding it, but they didn’t appear to be in sight. Now things look different.

Not only is Jeanne Calment’s life-span record unbroken, no one has come close to it since she passed on. While four “supercentenarians” reached at least 117 during the 1990s, no one has lived that long since 2000. (The second longest-lived person on record is Shigechiyo Izumi, who reportedly died in 1986 at age 120 and 237 days—there are doubts about his age at death, though.) Meanwhile, gains in life expectancy, or average life-span, appear to be flattening out—U.S. life expectancy rose by about 2% during each of the 1980s and 1990s, but over the past decade it has risen by about 1.6%.

As for running, you have to go back more than a century to find another era in which the world record for the mile stood for more than a decade. And some distance-running records have existed even longer than El Guerrouj’s. The high-school record for the mile (in a race including only high-schoolers) has stood for nearly a half century—it was set in 1965 by Kansan Jim Ryun, who won the Kansas High School State Meet that year with a time of 3:58.3. The collegiate records for the three-mile and the six-mile were set in the early 1970s by Steve Prefontaine, the storied University of Oregon runner who was tragically killed at age 24 in a 1975 car accident.

This isn’t to say we’re approaching hard and fast limits when it comes to longevity and running. But the marked slowing of gains in both realms of physical endeavor underscores a hard truth: We’ve gotten so many contributing factors right when it comes to longevity (reduced death from infectious diseases, better diets, improved geriatric care) and running (better conditioning routines, lighter shoes, faster track surfaces) that it seems we’ve nearly run out of ones that are crying out for improvement. To put it another way, making further substantial gains will require the simultaneous optimization of ever more factors that are already nearly optimal. (Such factors, by the way, include the extraordinary good luck of people who possess rare combinations of genes that abet extreme longevity or world-class running speed.) The killer issue is simultaneity—improving just one contributing factor may not be all that hard, but getting many of them more right than ever before is really, really tough.

When it comes to pushing the envelope on healthy life span, getting everything more right than ever means simultaneously lowering the risk of death from many hard-to-treat diseases of aging. That is, in the developed world we’ve already mostly eliminated early-life mortality risks, such as diphtheria and measles, and we’ve greatly cut mid-life ones too, such as fatal heart attacks before age 60, with preventatives such as hypertension drugs. In order to further boost life expectancy, we must now find a way to substantially lower the risk of death after age 75 from Alzheimer’s disease, all forms of cancer, Parkinson’s, heart failure, stroke, and many other killer diseases whose risk is not only quite high for people at such advanced ages, but also soaring even higher as they grow older. (And I’m focusing on life expectancy here because I think it’s a good proxy for what matters most: average health-span—no one wants to live an extra-long time in miserable health. Besides, rising life expectancy is tightly tied to the setting of longevity records, since it increases the number of extremely long-lived people who have a shot at setting a new record.)

A revealing 1990 study highlighted the daunting magnitude of this challenge. It showed that if we could totally wipe out cancer, U.S. life expectancy would rise by only about 3.2 years. (Based on 1985 actuarial data.) Eliminating all deaths from ischemic heart disease (the kind caused by clogged arteries) would yield a similarly small increase in life expectancy. The reason these gains would be surprisingly small is that numerous diseases are competing to kill us after 75, so even if we eliminated one of them, something else would soon get us and thus prevent life expectancy from rising very much. You can see from these startling figures that our current strategy of treating tough diseases of aging one at a time, often when it’s late and little can be done, isn’t likely buy us much in the way of quality time. And it’s obviously very difficult and expensive to attain even the relatively minor gains in average health- and life-span that we’re managing to eke out these days via the conventional, one-disease-at-a-time approach.

All this makes a compelling case for investing more of our medical-research dollars in anti-aging R & D. If we could slow aging in humans as much as we’ve already been able to in mice with an existing drug, we could increase average life-span at birth by about nine years. Do the math: This means developing drugs that modestly slow aging (which leading gerontologists say is now realistically achievable) would be like totally winning the war on cancer three times over. No other medical advance on the horizon promises such large gains in healthy life as anti-aging drugs do, because nothing else would so effectively deal with the killer issue of simultaneity mentioned earlier—almost by definition, decelerating the aging process would push off all fatal diseases of aging at the same time, as well as cut the age-associated risk of nonfatal ills, such as hearing loss and bone-thinning, that lower our quality of life as we get older. As a fringe benefit, anti-aging drugs would probably lead to a lot of new world records—including ones by middle-aged runners, for whom medicines that retard the loss of youthful speed and endurance, along with everything else that goes downhill as we age, would be the ultimate safe, performance-enhancement drugs.