In 1954, Denham Harman proposed the free radical theory of aging (FRTA), which posits that the accumulation of lipid, protein, and nucleic acid damage from free radicals results in a decline of function over time. Although the FRTA is one of the leading theories on aging today, it is still being modified. One major breakthrough was the identification of mitochondria as the major source of oxygen free radicals, such as superoxide and hydroxyl radical, and other reactive oxygen species (ROS), like hydrogen peroxide.

Support for the FRTA includes a decrease in ROS production in calorie restricted (CR) animals, a dietary strategy known to increase lifespan in a whole host of animals. A hot area of research is the search for calorie restriction mimetics, which mimic the lifespan extending effects of CR. By using CR mimetics therapeutically, we may be able to have lower cholesterol, blood glucose, and blood pressure, as well as lower instances of cancer, diabetes, neurodegeneration, and heart disease — and still be able to eat a hot fudge sundae every night.

Caldeira da Silva and Cerqueira suggest that mitochondrial uncoupling is an effective mimic of CR. In mitochondria, the electron transport chain uses electrons from glucose and lipids to pump protons across a membrane. This proton gradient can be used to make energy in the form of ATP through oxidative phosphorylation. The process is kind of like generating hydropower. Uncouplers work by putting a leak in the dam, which lets water through without going to the generator. They “uncouple” the electron transport chain from oxidative phosphorylation, thus reducing the efficiency of energy production. Although animals have uncoupling proteins (these proteins are important for thermogenesis, especially during hibernation), so far there are no known agonists. The researchers instead used low doses of the mitochondria uncoupler DNP. DNP was actually used as a diet pill because the body makes up for inefficient energy production by burning more fat. Unfortunately, all that potential energy in the proton gradient is released as heat, which can cause fatal fevers. (The FDA deemed DNP unfit for human consumption in 1938, although supplements are now sold online to bodybuilders).

Notably, the mice in the study had no change in body temperature. They were given doses 1000X below the lethal dose and plenty of space to let off any extra heat. The DNP treated mice ate the same amount of food as control mice but had lower body mass. The DNP treated mice showed many phenotypes observed in calorie restricted mice. Like CR mice, DNP treated mice had higher rates of respiration with lower production of ROS. These mice also had lower oxidative damage to their DNA and proteins, another hallmark of CR. They showed lowered blood glucose, lower triglycerides, and lower insulin. Most importantly, DNP treated mice showed an extended lifespan. This study suggests that mitochondrial uncouplers are an effective mimic of calorie restriction and might be a realistic therapeutic intervention for delaying aging and extending lifespan. Uncouplers may be even more effective than resveratrol, which may – or may not – only work on mice on a high fat diet.


Over the past decade, it has become increasingly clear that many aspects of aging are conserved across species. For example: the sirtuins, first discovered in yeast, control lifespan and age-related phenotypes in metazoans. Likewise, the IGF-1 pathway, originally revealed in the worm in studies of the daf-2 mutation, appears to play a significant role in mammalian aging.

But how much do these model systems reveal about what’s going on in human beings? Even the rodents — the laboratory organisms most closely related to us — have very different life histories and have adapted to very different niches over the course of evolution; therefore it would not be surprising if their response to e.g. calorie restriction (CR) were quite different from ours. Indeed, a study from Fontana et al. argues that this is the case for the IGF-1 pathway:

Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans

Reduced function mutations in the insulin/IGF-I signaling pathway increase maximal lifespan and health span in many species. Calorie restriction (CR) decreases serum IGF-1 concentration by ~40%, protects against cancer and slows aging in rodents. However, the long-term effects of CR with adequate nutrition on circulating IGF-1 levels in humans are unknown. Here we report data from two long-term CR studies (1 and 6 years) showing that severe CR without malnutrition did not change IGF-1 and IGF-1 : IGFBP-3 ratio levels in humans. In contrast, total and free IGF-1 concentrations were significantly lower in moderately protein-restricted individuals. Reducing protein intake from an average of 1.67 g kg−1 of body weight per day to 0.95 g kg−1 of body weight per day for 3 weeks in six volunteers practicing CR resulted in a reduction in serum IGF-1 from 194 ng mL−1 to 152 ng mL−1. These findings demonstrate that, unlike in rodents, long-term severe CR does not reduce serum IGF-1 concentration and IGF-1 : IGFBP-3 ratio in humans. In addition, our data provide evidence that protein intake is a key determinant of circulating IGF-1 levels in humans, and suggest that reduced protein intake may become an important component of anticancer and anti-aging dietary interventions.

To understand why this is significant and somewhat surprising, let’s go through the logic: Decreased IGF-1 levels are associated with increased lifespan. Calorie restriction is also associated with increased lifespan. In rodents, CR is associated with decreased IGF-1 levels, leading to the (still unproven) hypothesis that the effects of CR are mediated by modulation of the IGF-1 axis.

In humans, however, the situation is slightly different: As in rodents, the human IGF-1 pathway contains several genes that appear to regulate longevity. The longevity benefits of CR are still under study, but it does appear that certain types of fasting regimens have protective effects against e.g. tumor growth.

According to this new study, however, CR has no effect on the levels of functional, circulating IGF-1 — so while IGF-1 may regulate longevity and CR may protect against cancer and other age-related maladies, it doesn’t appear that CR mediates its effects via IGF-1. And this is true even in the model system that biogerontologists consider to be the best compromise between experimental tractability and evolutionary proximity.

The moral? Just that we can’t ever assume that a result obtained in rodents will hold true in humans: animal model results aren’t clinical facts, just hypothesis generators for studies that will ultimately have to be performed in Our Favorite Species. The devil, as always, is in the details.

As a biologist of aging, one question I get asked frequently is: “What should I be doing in the meantime?” That is, in the absence of any de facto anti-aging medicine, what’s the best way to extend healthspan, and thereby improve one’s chances of being around when bona fide life extension technology becomes available? Usually, the question takes the form, “What pills should I be popping?”

My answer (after issuing the routine qualifications that I’m not an MD, a dietitian or an exercise physiologist) is as follows: Vitamins are good but megadoses are of questionable value. Ditto for “supplements”: the nutraceutical industry is poorly regulated, so you don’t necessarily know what you’re getting. Beyond that, we don’t necessarily know the efficacy or understand the mechanism of action of many of these products, which means that we can’t begin to rationally predict the adverse reactions that could result from their combination.

Kind of bleak, right? Turns out that I do have some constructive advice, however — and it’s the same advice you’ve been getting all your life: Avoid tobacco, eat a reasonable diet, and get plenty of exercise. After all, I usually jest, they’re never going to turn exercise into a pill.

That is, until they do.

Enter the era of PPARβ/δ and AMPK agonists. From Narkar et al.:

AMPK and PPARδ Agonists Are Exercise Mimetics

The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARβ/δ agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1α, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARδ pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.

Get that? Mice that performed no workout more taxing than taking their medicine were almost 50% better than controls at running — and the effects were even more dramatic when combined with actual exercise.

Assuming — standard caveat — that AMPK agonists like AICAR are efficacious in humans, the potential applications are tremendous, with potential benefits for everyone from bedridden hospital patients to astronauts at the ISS.

An interesting open question: We know that actual exercise extends lifespan, possibly via hormesis (the improvement of chronic stress tolerance in response to regular acute stress). Do the exercise-like effects of PPARβ/δ and AMPK agonists also increase longevity — and if so, does the mechanism involve hormesis? In other words, are these drugs increasing endurance by simulating the acute stress of exercise, or are they activating a response further downstream in the pathway?