Guardians of the Healthspan

In a few mouse models, upregulation of sirtuin was found to extend life, but most mouse studies produced only a healthier life, not a longer one, thus earning sirtuins the title guardians of the healthspan in mammals. Sirtuin activation not only preserves the integrity of DNA but improves DNA repair, curbs inflammation, and helps maintain telomeres, which I discuss in the next chapter. This shows up in better blood sugar values and denser bone mass, less DNA damage and cancer. Therefore, in the few cases in which lifespan was extended, it may have been more about suppressing age-related diseases than slowing the rate of aging per se. In any case, these effects were observed in mice and still need to be confirmed in humans. We do know, however, that in humans there is no connection between an extraordinarily long life and the presence of one of the variants of at least one sirtuin gene. As one critic mused, sirtuins may have lost their Methuselah image, but can still be a helpful metabolic Samaritan.

As you may recall, the fuel-gauge enzyme I talked about in the AMPK chapter increases sirtuin activity. Therefore, activating AMPK through metformin, calorie restriction, or exercise can lead to sirtuin activation. But since revving up sirtuins is an indirect effect of AMPK, it blunts the sirtuin response to exercise if you guzzle sugar water

for example, a sports or energy drink

before a sprint. While mild calorie restriction

around 15 percent, about 350 calories a day

had no effect on sirtuin activity, a 30-percent calorie reduction over eight weeks did, but not in five days. By contrast, Buchinger fasting (in which you drink only certain juices and vegetable broth) can increase sirtuin activity within five days, as can three weeks of alternate-day fasting, going down to 1000 calories a day for a month, or six months at 25-percent calorie restriction.

AMPK increases sirtuin activity by increasing the amount of cellular nicotinamide adenine dinucleotide (NAD+). NAD+ is a critical cofactor required for sirtuin activity. Alternative methods of raising NAD+ levels include taking a number of NAD+ precursors, as I show in the section on the anti-aging eight. Raising NAD+ levels is one of two basic approaches to stimulating sirtuins. The other works through STACs, sirtuin-activating compounds, the best known of which is resveratrol, a natural substance found in concentrated form in grape skins.

Resveratrol

Resveratrol, the red wine molecule, has been on everyone's lips since 1991. That was when a scientist from the University of Bordeaux appeared on the popular TV show 60 Minutes and attributed the so-called French paradox to the French habit of drinking red wine. As you can see at see.nf/resveratrol, the paradox has been successfully debunked, though not before resveratrol research had already become established and culminated

to this day

in more than 15 000 scientific publications.

As I show in the video, the animal trial data are mixed. For example, resveratrol extends the lives of worms and bees, but not those of flies or fleas. Unfortunately, most studies in mammals (mainly mice) showed no lifespan benefit. Even its alleged sirtuin activity has been called into question. Articles with titles like Resveratrol—a fraud? and Promising therapy or hopeless illusion? were published and claimed that the apparent sirtuin activity was probably the result of a measurement error. The fact that a leading resveratrol researcher was found guilty in 145 cases of fabricating and falsifying data, throwing the entire research field into turmoil, did not help matters either.

In a 2014 editorial in a medical journal titled The Resveratrol Debacle, the editor-in-chief summarized the state of the research: The conclusions are quite clear: After more than 20 years of robust research, there is no evidence that resveratrol works in humans. However, since that article, over 150 clinical trials in humans have been published. I show the update in see.nf/resveratrolhealth. Epidemiologically, no effect was found of dietary resveratrol intake on inflammation, cancer, cardiovascular disease, long-term frailty, or death, and meta-analyses of randomized controlled trials of resveratrol supplements recorded no clinically or statistically significant effects on systemic markers of oxidative stress that would have explained any visible DNA protection.

For nearly all outcomes measured in randomized controlled trials of type 2 diabetes, metabolic syndrome, or nonalcoholic fatty liver disease, the effect of resveratrol was, at best, trivial, but one meta-analysis found that doses of 5 to 500 milligrams twice a day led to an average drop of 20 points in fasting blood sugar. There was also a significant effect on long-term blood sugar regulation (HbA1c), although this was only the case in shorter-term studies. What good is it for long-term regulation if resveratrol only works in studies lasting less than three months? Well, one study pointed to accelerated wound healing in diabetic foot ulcers, a major cause of lower-extremity amputations.

In see.nf/resveratrolclinical I go through what else resveratrol supplementation might accomplish clinically. In rats and mice, resveratrol can help mitigate the effects of experimentally induced periodontitis, the inflammatory gum disease. In humans, however, it appeared to have no effect on the progression of chronic periodontitis. At least resveratrol had a supportive effect in the inflammatory bowel disease ulcerative colitis, and in knee osteoarthritis.

Resveratrol shows some estrogen-like activity, and although it does not help with hormone-related migraines, it does apparently help with a few symptoms of polycystic ovary syndrome (PCOS) and menopause. Unfortunately, a meta-analysis of studies of resveratrol supplementation to improve bone quality found no significant effect on measures of bone health or bone mineral density of the spine, the hip, or the skeleton overall. The same was true for cognitive effects, which is why a systematic review suggested that resveratrol might improve cognition only in mice. The largest study on resveratrol and Alzheimer's even measured three times more brain shrinkage in participants randomized to the resveratrol group than in the placebo group.

Negative or disappointing findings are often pushed to the margins by the resveratrol research community. As I summarize in see.nf/resveratrolsafety, no long-term safety data exist, yet even with supplementation that is purportedly safe (150 to 250 mg daily), resveratrol was found to possibly dampen some of the positive effects of exercise and undermine physical fitness in young and old.

A recently published article overreacted to these data and claimed that foods containing resveratrol should not be eaten when exercising, but to even reach the lower dose of 150 milligrams, one would have to eat over 100 pounds of grapes. The impairment of exercise performance with resveratrol supplementation is, however, logical in light of its purported mechanism. It is thought that sirtuin activation by resveratrol works via activation of AMPK, the body's fuel gauge, by hampering energy production in the mitochondria of our cells. Mouse cells compensate for this by producing more mitochondria, but human cells apparently do not, so the energy-dampening effect of resveratrol may explain why the training effect is impaired.