You don’t want a sluggish metabolism… or even a fast metabolism. You want a flexible metabolism capable of switching fuels rapidly. Here’s how to get it.
I’m driving around Los Angeles and I’m annoyed. Not the conscious type of annoyed where I’m irate at the driver in front of me, but more the subconscious type of antsy where you unknowingly grit your teeth and stiffen your muscles.
I feel my back locking up and begin shifting back and forth in my seat to alleviate the pain. And damn, now I have to pee. I’m squirming around in my seat like an overzealous chihuahua. I’ve moved only a mile in the last 15 minutes. Nothing I can do. I’m stuck in traffic and it sucks.
Forty-five minutes later, I’m driving out of LA, heading across the country. The highway opens up, and for the first time I can actually travel the speed limit. I take a deep breath and relax. My back feels fine. I either imagined the need to pee or accidentally pissed my pants. I’m not sitting in a puddle, so apparently I just needed to freakin’ relax.
A week later I’m in North Carolina. I just arrived in a sleepy town called Asheville where the traffic is light everywhere. This is how I spend my year. Three months at a time in Santa Monica and three months at a time in Asheville.
That story is a perfect metaphor for something called “metabolic flexibility.”
You have two major fuels you burn: carbs and fat (glucose and fatty acids for you biochemistry types). You can burn a few other fuels too, like protein and ketones.
But the body doesn’t like to use protein because it’s an expensive fuel (it uses a lot of energy to burn) and inconvenient – the body would like to keep it for the purpose of moving around and lifting things. You can also burn ketones, but that’s contingent on you being able to handle fat.
We can’t forget about alcohol. It provides energy (7 calories per gram), but takes up space in your metabolic machinery. It’s a source of acetyl-CoA, which is the same endpoint of fat and sugar breakdown. Alcohol arrives at this step faster, so including a lot of alcohol in your diet interferes with burning these other fuels. When the metabolism sees a lot of acetyl-CoA showing up, it sees no reason to continue burning fat or sugar. Alcohol makes your metabolism less flexible.
You can think of alcohol as 18-wheeler semi-trucks, carbs as SUVs, and fat as sedans. Sedans are what you mostly see on the road and in parking lots. It would be great if they could move around freely, but the semis and SUVs often get in the way. In other words, if burning fat is what you want, then you better be able to handle sugar and alcohol.
What about protein and ketones? What are they in this analogy? Protein is versatile (enters energy production at many steps besides acetyl-CoA) but costly and inconvenient. It’s a lot like a motorcycle, bicycle, Uber or one of those Bird ride-share electric scooters. They can help you weave in and out of traffic, but suck if you get caught in the rain.
Ketones are like public transport. When ketones are ramped up and efficient it makes the rest of the highway less congested.
Metabolic flexibility is the ability to switch from one fuel to the other quickly based on food availability and fuel demand. In the traffic analogy, metabolic flexibility gives you green lights for 20 blocks and wide-open highways.
In food terms, it means you can eat a large bowl of Cinnamon Toast Crunch in the morning and your metabolism will barely work up a sweat (ask any active teenager). Metabolic flexibility means nothing but bacon and eggs for breakfast while your metabolism hums right along.
Being metabolically flexible means you can endure 2.5 hours of afternoon football practice with nothing but a single burnt egg for breakfast and an unpeeled grapefruit in a brown paper bag for lunch. A healthy, flexible metabolism should be able to handle all of these demands and more.
Metabolic inflexibility means one or more of the metabolism’s energy pathways are compromised. It means there’s a parade, a semi-truck convention, the Super Bowl, and massive construction on the i405 all in the same weekend.
An inflexible metabolism is one that’s fat, tired, irritated, and hungry despite being well fed. It’s metabolic gridlock at the level of your mitochondria – too much fuel trying to get in and not enough energy being pumped back out.
You want a flexible metabolism instead. You don’t want Usain Bolt unless he can jump hurdles, do handstands, and juggle flaming swords too. A flexible metabolism is a great multitasker. It’s not just good at burning sugar; it excels at burning fat too.
So how do we get a flexible metabolism? Before we can understand that, we need to understand what’s causing inflexibility in the first place. Research in the last few years has clued us in as to what’s going on with the metabolism. For many years we’ve taken a top-down approach.
The top-down approach goes like this:
- Macronutrients and calorie loads have hormonal effects.
- Too much carbohydrate leads to high amounts of insulin. (Too many calories and too much protein does too.)
- Very high insulin all the time causes the body to stop responding to insulin (insulin resistance).
- Chronically high cortisol can also lead to insulin resistance. (Can you say stress?)
- Insulin resistance leads to the inability for fat and sugar to enter cells to be burned.
- Fat and sugar (triglycerides and glucose) end up hanging out in your blood doing damage and/or getting restored.
Sound familiar? But there’s also a bottom-up effect we’re starting to understand.
It goes like this:
- High amounts of energy from multiple, huge mixed meals arrive at the mitochondria all at once.
- The mitochondria work overtime with no breaks and start seeing faltering nutritional resources.
- High amounts of free radicals (mainly hydrogen peroxide) damage mitochondrial membranes and cause changes in DNA (acetylation, etc.)
- Depleted cofactors and signaling molecules needed for mitochondrial function (NAD+, glutathione, carnitine) lead to a slowdown in energy production.
- The slowdown in mitochondrial function, the damaged mitochondrial integrity, and the excess energy precursors from fat, carb, and alcohol cause a backup of fat and sugar metabolites.
- Acetyl-CoA from excess fat breakdown blocks the burning of carbs.
- Acetyl-CoA from excess sugar breakdown blocks the burning of fats.
- Alcohol acetyl-CoA blocks the breakdown of both fat and carbs.
- Cellular function starts to break down.
- Insulin receptor function becomes compromised as a result.
- Bottom-up insulin resistance ensues. Blood sugar rises. Blood fats (triglycerides) rise.
- Top-down insulin resistance kicks in now as well.
You turn into a fat, tired, snoring, depressed, anxious person who cries if your spouse gets to the Ben & Jerry’s before you do.
Now, those bullet points are handy but let’s not miss the organizing context. When fat, sugar, and alcohol are metabolized, their breakdown products converge at acetyl-CoA. Protein is a bit different since it can enter metabolic energy pathways at many different places.
One thing to understand about metabolism is that it’s NOT a very good multitasker when it comes to burning fuel. It functions most efficiently when one fuel is dominating over another. One way we understand this biochemically is from the way an energy-burning pathway creates multiple signaling molecules that block the other pathway.
For example, when you burn fat you create many different compounds that suppress the key regulatory enzymes that run the sugar-burning pathway (such a pyruvate dehydrogenase PDH, and phosphofructokinase PFK). And the reverse is true as well – when you burn sugar you create molecules that block fat-burning pathways.
The respective pathways for fat and sugar burning inhibit one another so that…
- If you eat more fat it blocks some of your sugar-burning regulatory steps.
- If you eat more carbs it’ll block some of your fat-burning regulatory steps.
- If you eat large amounts of both in combination, neither pathway runs as efficiently as it could. (See The Food Combo That Makes You Fat.)
Too much of either fuel can lead to insulin resistance. Eating too much sugar most often leads to a top-down effect where insulin kinetics end up being compromised; insulin resistance kicks in and entry of fuel into the cell is slowed down.
Excess fat is more likely to create a bottom-up effect. The breakdown of fat generates a huge amount of carbons. This overwhelms the mitochondria creating dysfunctional mitochondria (a change from connected to more dispersed mitochondria) and inflexible mitochondria (competitive inhibition of the sugar-burning pathways).
This causes decreased cellular energy production and increased reactive oxygen molecules which can have a negative impact on cellular protein production and function, including compromised insulin receptor sensitivity. That leads to insulin resistance and decreased fuel entry into cells.
This is why the hallmark of metabolic inflexibility is “metabolic syndrome.” That’s where both fasting sugar (glucose) and fasting blood fats (triglycerides) are elevated.
The especially upsetting aspect of this metabolic conundrum is that lipolysis (the breakdown of fat) and glycogenolysis (the breakdown of stored glucose) may still occur, especially during times of need (i.e. exercise). However, the ability to burn those fuels remains compromised because release of fat and sugar is but one step in a four-step process of fuel burning.
That process goes like this:
- Release the fuel from where it’s stored – lipolysis, the breakdown and release of fat from its storage depots.
- Shuttle the fuel to the cells that need it. (Blood flow is important here.)
- Get the fuel into those cells. Here’s where the insulin receptor comes in.
- Burn the fuel in the cell – i.e. fatty acid oxidation is the act of fat being burned in the mitochondria.
In metabolic inflexibility, the defect occurs at either step 3 (top-down effect), step 4 (bottom-up effect), or both. Which is more important, top-down or bottom-up, is something science is still working on. That’s bound to be a complex story of interactions between genetics and environment. What we do know is that both are involved, and this gives us some great tools to use.
Perhaps you’re thinking all this is just another way of describing people eating too much. You wouldn’t be wrong, but it also may explain why one of my friends, a 200-pound bodybuilder, can consume 4000 calories and remain lean, while another one of my friends, a 225-pound recreational lifter, gets fat if he goes much above 2500 calories.
Besides that, if people could follow the “eat less” advice, we wouldn’t be having this discussion. The fact is, they can’t. And part of the reason is metabolic inflexibility. Having a non-flexible metabolism not only changes the way we burn fuel, but also causes us to crave more and eat more.
Our ancestral way of living is a good place to start with understanding the way back to a functional metabolism. First off, we humans evolved as hunter-gatherers:
- Sometimes we ate what we gathered because the hunt wasn’t successful.
- Sometimes we ate only what we hunted because gathering was unsuccessful (think winter).
- And we surely sometimes ate both.
We also ate fewer calories and lower amounts of both fat or sugar. In addition, we probably had more distinct separation between macronutrient intake. Fruits and tubers, our natural sugar sources, were only available at certain times of the year and we didn’t have the tools to harvest wheat and bake bread. Wild animals aren’t super fatty. Fatty vegetable foods are mostly seasonal.
Couple that with much longer times asleep (we slept when the sun went down and woke when it rose) and lots of walking and you can see why being metabolically flexible was a major survival advantage and a natural consequence of living in alignment with natural cycles.
A Paleolithic dinner, which was likely the biggest and usually only meal of the day, was not an affair of passing the corn, going for seconds on the brisket, and “can I have one more piece of key lime pie, please.” It was more likely a dinner that consisted solely of deer meat and a few dried blueberries.
Becoming metabolically flexible means there are a few things we can do that came naturally to our ancestors.
You want some off-the-shelf strategies and tools to use, right? Well, what you need to understand is the perfect approach isn’t perfect if you can’t stick to it.
Think about it: Fasting might be ideal for every human on the planet, and if there wasn’t a fast food joint and supermarket on every corner, it would be feasible. The fact is some people who begin a fast in the morning will end up binging in the evening, making their situation much worse.
I have four food approaches that I feel best address metabolic flexibility, and I’ve listed them from beginner to advanced. It’s useful to remember, the metabolically inflexible are often the people most at risk for issues with sleep, hunger, mood, energy, and cravings. I abbreviate this SHMEC, pronounced “shmeck.”
A person with a SHMEC out of check is a metabolically inflexible person and should start slowly working their way down the diet interventions below from basic to more advanced.
Remember, we’re ultimately trying to prevent metabolic gridlock at the level of the mitochondria. Fat and carbohydrate approaches to dieting may not be good for beginners with metabolic inflexibility. These people tend not to be able to burn either fat or sugar appropriately and also suffer from unrelenting hunger, energy lows, and cravings.
Just take a look at this chart from a study published in the American Journal of Clinical Nutrition titled, “Fat and Carbohydrate Balances During Adaptation to a High Fat Diet.” In the chart, RQ is a measure of fat versus carb use. The higher the number the more carbs burned and the lower the number the more fat burned.
You can see there’s extreme variation, which is likely (at least partly) due to metabolic flexibility differences between subjects. This is why one-size-fits-all diets simply don’t work. It’s also why cold-turkey keto diets and intermittent fasting fail so many beginners. Their metabolisms are simply not flexible enough to handle it yet, and the initial week of transition is often too miserable for most people to get through.
For these types, small frequent meals keep them from binge eating. A focus on protein and fiber over fat and starch/sugar clears the mitochondrial highways, allowing repair. This is an old bodybuilding approach and works very well for dieting beginners, and for those for whom skipping meals can result in severe binge eating.
This approach has the added advantage of more “food interaction” for people. It teaches a lot about calorie levels in foods, macronutrient content, and food preparation. I’ve found most successful individuals, who have gone from fat to fit and stayed there, had their journey pass through this stage. I’ve come to see it as a necessary part of the journey for many.
Once metabolic flexibility is restored to a degree, it’s feasible and doable to go further with less frequent eating regimes like fasting, or single macronutrient regimes like keto. It’s useful to also point out some science here. The three big meals a day approach is more detrimental for metabolic control and flexibility compared to more frequent smaller meals. Remember, we’re trying to reduce metabolic gridlock. Smaller meals avoid the metabolic traffic jams big meals may cause.
After regaining some metabolic flexibility, one can begin to focus on one type of food or the other, not both. Mitochondrial overwhelm happens when you eat all the fuels, in large amounts.
This may be why ketogenic diets and vegan diets both show benefit in metabolic parameters like insulin resistance. One is mostly carb and lower fat; the other is mostly fat and lower carb. Both diets move the metabolism out of its need for multitasking and allow it to run and optimize one pathway.
This is the metabolic equivalent of trying to drive on congested city streets compared to driving on free-flowing highways. By separating fuels in this way we can wake up the metabolic pathways.
This may be a true benefit of a keto diet. One hidden, often neglected aspect of a keto diet is that it’s a “one-flavor diet” – all savory and creamy. Diets that are more singular in flavor (bland) have been shown to shut down hunger due to the neural feedback networks in the brain decreasing hedonistic food seeking behavior.
Another approach is to spend a lot of time not eating anything. A gentler way to start fasting is to spend equal time not eating as eating. Twelve hours with food and twelve hours without food at a minimum.
That isn’t a very difficult behavior change for most people to make given most of the “not eating” part happens while asleep. As you regain metabolic flexibility this will become easier. A metabolically flexible person should be able to go long periods of time without eating. As you adapt, you may want to experiment with longer periods without food (16 to 24 hours).
This is likely the fastest and most natural way of restoring metabolic flexibility. It’s also the one that can cause the most negative reactions in someone NOT metabolically flexible.
Our ancestors could not have consumed 4,000 calories at a meal if they tried. One meal with dessert at a Cheesecake Factory and we could easily achieve that. The drive for food is one of the most powerful drives in all physiology (sex being the other). What’s worse is the metabolically inflexible person is far more likely to overconsume food and far less likely to be able to handle that food. So this approach simply doesn’t work as a starting place for most people.
In metabolic research there’s a measurement called the Respiratory Exchange Ratio (RER or RQ). You saw that above in the chart. This is the amount of Co2 you expire to O2 you take in. This is a way to measure the amount of carbs versus fat you’re burning. More CO2, more carbs. More O2, more fat. This number ranges from 1.0 (all carb burning) to .7 (all fat burning).
The fuel you eat the most is roughly equivalent to the RER at rest. The fuel you burn during exercise is mostly correlated to the opposite fuel burned when not exercising. In simple terms this means when you eat fat you burn more fat at rest, and when you burn fat during exercise you burn more carbs at rest.
This is important to remember when you think of combining diet and movement strategies. If you want to be a better fat burner, you want to do exercise that uses more of the sugar pathways and fuel that exercise with more sugar. So, high intensity exercise may mean you want to eat more carbs around that time.
Or think of it in the reverse direction: if you’re eating more carbs, then more intense exercise is in order. I call this an “Eat More, Exercise More” approach or EMEM.
By the same token, if you’re eating more fat then you may want to do much lower intensity exercise. For all but the most fat-adapted athletes, very low-carb keto diets pair best with less intense movement like walking. I call this an “Eat Less, Exercise Less” approach or ELEL.
Of course calories matter, so the EMEM and ELEL approaches hold true whether you are opting for single macronutrient diets or low-calorie mixed diets. The difference is that EMEM creates your calorie deficit through exercise and ELEL creates the deficit through food. Both work because they force the body to be more flexible and subject it to less extreme calorie deficits and, therefore, less stress.
Eating More and Exercising Less (EMEL, the couch potato) can easily overwhelm the mitochondrial pathways from both a top-down and bottom-up effect. Eating Less and Exercising More (ELEM, the dieter) can often create too much stress leading to compensatory eating reactions and stress-induced insulin resistance.
The best approach for flexibility means looking at each of these as different metabolic toggles you can pull:
- ELEL is the winter toggle.
- EMEM is the late spring through early fall toggle.
- ELEM is the early spring toggle (a few weeks).
- EMEL is the late fall toggle (a few weeks).
The metabolism is nothing but one big stress barometer. Its job is to sense what’s going on in the outside world, measure the amount of stress present, and relay that info to cells inside.
It does this by using hormones, and this hormonal system can also be negatively impacted by both the top-down and bottom-up mechanism of metabolic inflexibility. Sleep, movement, exercise, stress, and temperature are all mostly under our control.
You can eat your way to metabolic inflexibility or you can stress your way there.
The stress hormones (cortisol, adrenaline) are all about liberating fuel. If you’re sitting at your cubicle stressing your ass off, you’ll release sugar and fats into your blood stream. In a perfect world you’d burn that stuff up through fighting or fleeing. In today’s world all that fuel may get released, but it doesn’t get burned. That can have top-down and bottom-up metabolic consequences.
Cortisol especially seems to have several nasty effects. It decreases the motivation centers of the brain and increases the reward centers. It also may have a role in making us eat larger meals.
Sleep issues can immediately make insulin resistance worse and have all the negative effects of stress above.
This is different than exercise. We know this because metabolic research makes a distinction between Exercise Associated Energy (EAT) use and Non-Exercise Associated Energy use (NEAT).
EAT is only 5% of changeable metabolism while NEAT is 15-20%. NEAT (walking and other activities of daily living) also has multiple top-down and bottom-up effects by clearing the fat-burning pathways, increasing glucose receptors without the need for insulin, and lowering cortisol.
This is a great tool, but it’s over-relied on and can’t, by itself, fully overcome metabolic inflexibility issues.
At best, exercise creates a transient state of metabolic flexibility. In our traffic congestion analogy, exercise is a lot like an emergency response vehicle that clears out traffic so it can get by. If you’re lucky enough to get right behind it, it’s clear sailing for you. For most people, after the vehicle passes, the traffic gets gridlocked once more.
This is why the old mantra of “you can’t out-train a poor diet” is very true. “Exercise snacking,” the idea of doing brief bouts of intense exercise prior to or after a meal can help. A 2008 review by Thyfault, et al. showed that one session of intense exercise can dramatically increase muscle insulin sensitivity for the next 24 hours.
It makes a difference, and we know that adjustments to cold and hot temperatures can increase metabolic flexibility.
Energy is used and metabolic pathways are exercised when our metabolisms are forced to respond to temperature challenges. This is why you may want to adjust your thermostat in your house and train in natural temperatures at the gym.
Cold sleep temperatures, hot training temperatures, and hot and cold immersion therapies may have a role to play in the development of more metabolically flexible brown fat as opposed to more metabolically inflexible white adipose.
You can think of the mitochondria as the “little engines that could.” They take in fuel and burn it. Mitochondria that are overloaded and damaged are a lot like that beat-up old jalopy that backfires, spews black smoke, and sputters along.
In this analogy, the “black smoke” is hydrogen peroxide, which damages cellular machinery (and one of the reasons your beard is going gray), and the sputtering is your constant irritability, hunger, and unpredictable energy.
Clean burning, efficient mitochondria are a lot like those brand spanking new electric Teslas that you can barely hear and can blow a sports car away in terms of speed and performance. This is analogous to predictable stable energy, decreased hunger, optimal performance in the gym, and optimal recovery from the gym.
Turning your jalopy into a Tesla is something you may need help with, and there are a few supplements that can make a difference:
Part of the long-term changes in mitochondrial dysfunction and metabolic flexibility come from adjustments to the mitochondrial DNA, like acetylation and other chemical reactions that impede mitochondrial function in a feed-forward negative cycle.
Glutathione is like a cool wet sponge that neutralizes the hot sticky mess of mitochondrial radicals. The best and cheapest place to get this supplement is not from glutathione itself – it’s not well absorbed. Whey protein (on Amazon) is a rich source of glutathione precursors and is a well-established booster of glutathione in studies. Whey protein is cheap insurance your cellular machinery isn’t being ripped to shreds by vicious free radical metabolites.
Another important multitasking nutrient is alpha-lipoic-acid. It acts as both a water-soluble and fat-soluble antioxidant, which means it can decrease metabolic damage from free radicals in the cell’s cytosol (water-soluble) and in the inner mitochondrial membranes where all the metabolic action is happening (fat-soluble). It also keeps our glutathione around longer.
The next one is carnitine, specifically acetyl-L-Carnitine (ALCAR). There isn’t a whole lot to expand on with this one. The attachment of the acetyl group allows this molecule to more directly impact the mitochondria where it’s needed to shuttle fats into the inner fat burning machinery.
Carnitine, like alpha lipoic acid, is also a wonderful buffer against some of the metabolic smoke (i.e. damaging free radicals) produced by metabolic inflexibility.
This compound plays a dual role as an energy precursor and a signaling molecule inside the mitochondria. It’s an integral part of energy production in the mitochondria by acting as a precursor to NADH, which is a key molecule that shuttles electrons from one part of the mitochondria to the other.
As NAD+ levels fall through metabolic gridlock, NADH levels also become compromised and mitochondrial efficiency wears down. Adding NAD+ to the mix enhances the mitochondrial machinery in an acute sense. But it also acts as a molecule that signals important information to the metabolic auto parts store (i.e. DNA).
NAD+ helps protect DNA from damage in multiple ways, including elevating SIRT function. For the non-biochemists, SIRT is an abbreviation for sirtuin, and the sirtuins are one of our most important anti-aging compounds. They keep our metabolism flexible into old age. You can think of NAD+ as getting an upgrade to your car’s engine, while at the same time upgrading to top-of-the-line tires and a new, more resilient cage and body.
The best way to develop a flexible metabolism is to eat and train in different ways, not the same ways. If you’re a fat eater spend some time eating carbs. If you’re a runner spend some time doing weights. And vice versa.
To train the metabolism, challenge the metabolism. This is the real utility of fasting, keto, intervals, refeeds, and all the rest. Those who do the same stay the same.
- It’s not about having a fast metabolism; it’s about having a more flexible metabolism.
- Metabolic flexibility refers to the metabolism’s ability to switch quickly and efficiently between fuels based on availability (i.e. what’s to eat) versus demand (what our activity requires).
- The two major fuels we burn are fat and sugar/glucose. But we can also burn protein and ketones, and use alcohol.
- On our metabolic highway, alcohol is like big semi-trucks – it really gets in the way of smooth flowing traffic. Sugar is like SUVs – they’re a little bit of a pain on the highway, but only because there are so many of them. (In other words, most people over-consume sugar.) Fat is like sedans.
- Protein is like Uber, bicycles, motorcycles, and rental electric scooters. Focus on eating protein and you’ll decrease some of the metabolic burden on the highways. Protein satiates so you eat less calories overall and it has many different locations besides acetyl-CoA to enter the body’s energy pathways.
- Ketones are a lot like public transportation. It’s not easy for most people to enter ketosis, but once they do their metabolic highways are relieved of a lot of congestion.
- Metabolic inflexibility comes from a top-down (food or stress causing insulin resistance) or bottom-up (mitochondrial overwhelm leading to insulin resistance) effect.
- Fasting, eating small frequent meals lower in carbs and fat, going vegan, or going keto can all help restore metabolic flexibility, but should be approached based on individual preference and tolerance.
- Cycling the diet and watching stress and sleep are important.
- Exercise, movement, and temperature exposures need to be understood and utilized.
- Supplements like whey, alpha lipoic acid, carnitine and NAD+ can aid metabolic flexibility.
Okay, so I know that was a lot to process. It’s a HUGE topic that could fill a few books. It’s also an area that needs much more inquiry. What I did above was try to give you a framework to wrap your head around. For the more sophisticated biochemistry buffs, I recommend reading the four articles in the reference section.
- Smith RL et al. Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease. Endocrine Reviews. 2018 Aug 1;39(4):489-517. PubMed.
- Galgani JE et al. Metabolic flexibility and insulin resistance. American Journal of Physioliogy Endocrinology & Metabolism. 2008 Nov;295(5):E1009-17. PubMed.
- Goodpasture BH et al. Metabolic Flexibility in Health and Disease. Cell Metabolism. 2017 May 2;25(5):1027-1036. PubMed.
- Muoio DM. Metabolic inflexibility: when mitochondrial indecision leads to metabolic gridlock. Cell. 2014 Dec 4;159(6):1253-62. PubMed.