In an Age of Epigenetics, Does Antagonistic Pleiotropy Still Make Sense?

The dominant theory of aging today was conceived at a time when genes were thought to be biological destiny.  Handiwork of George Williams, it is called Antagonistic Pleiotropy.  Pleiotropy is the idea that one gene can have multiple effects, and the core of the AP theory is that there are genes that give us strength and fertility in youth, but they cause havoc later in life, ultimately destroying the body.  Fifty years after Williams, we now know that genes are routinely turned on when and where they are needed, and turned off most of the time.  More than 97% of our genome is devoted not to genes but to epigenetics, which is the regulation of gene expression, and a mainstay of 21st century molecular biology.  Why should the body ever be stuck with a gene that is doing it harm?   Can antagonistic pleiotropy be re-cast to make sense in this age of epigenetics?  

In 1957, George Williams proposed an evolutionary theory of aging that later became known as Antagonistic Pleiotropy, and under than name has been the most influential theory of aging to this day.  It has formed the basis for interpreting a huge variety of phenomena in aging labs around the world.  Pleiotropy is routinely invoked to explain results in genetics, and “evolutionary medicine” is guiding (or misguiding) research priorities for the future of anti-aging science.

Williams began with the idea (still dominant today) that rapid and copious reproductive output is the ticket for evolutionary success.  A mathematical measure of time-weighted reproduction is the Malthusian Parameter r, which Williams assumed (many today agree) is as good a mathematical translation as we have for Darwin’s concept of “fitness”.

I have argued that there is more to fitness than reproducing as fast as possible. The very word “fit” came from the notion of traits appropriate to a particular environment, a particular ecosystem.  Ecological consequences can’t be separated from individual fitness.  Any individual that achieves a growth rate (r) that is higher than species further down the food chain has only a very short-term fitness advantage, because its grandchildren risk starvation.  I’ve written about fitness in an ecological context here and in my new book.

Genes “your way”!  Tucked away when you don’t need ’em

Today, I am offering another reason to discredit antagonistic pleiotropy.  Williams’s theory is rooted in the idea that if a gene is selected in evolution for its advantage early in life, then the bearer of that gene is stuck with it late in life as well.  Now that we know how routinely genes are turned on and off in particular tissues, at particular times, for just a few minutes or for years on end, it is no longer credible to imagine that the individual is stuck with a gene at a time when it has become a liability.  Can we find a way to make sense of antagonistic pleiotropy in the context of complex and robust epigenetic adaptation?

I’ll say this much for pleiotropy: some of the genes most detrimental to the body do indeed have “legitimate” functions (good for the individual or her reproduction).  I have come to see the proximate cause of aging as a re-balancing of hormones, some turned up and some turned down, with detrimental effect.  Inflammation is turned up too high.  Apoptosis is turned up generally, causing loss of perfectly good muscle and nerve cells, but the strong apoptosis signals that kill cancer cells before they can become tumors becomes less effective with age.  Melatonin (for the circadian clock) and glutathione (antioxidant) and CoQ10 (cellular energy) are all in progressively shorter supply as we age.

It is common to call this rebalancing “dysregulation” and ask what went wrong [example, another, a third].  But I don’t think evolution makes such big mistakes.  I see not dysregulation but  re-regulation or even re-purposing of a system that protects the body, toward the end of self-destruction.

Mikhail Blagosklonny has written often about a theory in which aging comes from the body’s inability to turn off the genetic program that led to development and growth early in life.  He knows his stuff, and writes convincingly about particular genes (notably mTOR) and the evidence that they are being kept on later in life, when their main consequence is to increase inflammation, promote disease and shorten lifespan.  I question only the part of Blagosklonny’s theory that says this is an accident.  I see it as one of the many instances in which genetic machinery is repurposed.  How does Blagosklonny explain this mistake?  “A potential switch that would turn off the developmental program cannot be selected, because most animals die from accidental death before they have a chance to die from senescence. A program for development cannot be switched off, simply because there is no selective pressure against aging.”  This idea has a venerable past, but no future.  Indeed, there is selective pressure against aging, and the cost of aging in the wild can be as high as 70% of fitness, though it is typically about 20-30% [ref].  This idea that aging comes about because no animals in the wild live long enough to die of old age was a brilliant insight due to a Nobel immunologist sixty years ago; but today it is no longer tenable.

Oft-cited Example of Antagonistic Pleiotropy

A classic example used to illustrate pleiotropy is Huntington’s Disease.  This is a congenital syndrome caused by a gene variant that actually increases fertility early in life, but typically around age 40, neurological symptoms begin, affecting coordination and causing mood swings.   Brain cells die, and Huntington’s is eventually fatal.  Huntington’s is not normal aging, of course, but the idea is that there are other genetic variants that are so common we don’t think of them as diseases but they are also promoting fertility early in life and degeneration later on.

In this case, it is not the timing of the gene but the version of the gene (allele) that is caused.  Is Huntington’s Disease truly an example of antagonistic pleiotropy?  Yes, in the sense that the allele causing Huntington’s Disease has both a benefit and a cost, and the cost is connected to disease and death later in life.  But no, in the sense that natural selection has actually rejected the Huntington’s gene time and again.  The Huntington’s mutation is one that occurs spontaneously in one child, and then is transmitted to children and grandchildren.  It lasts for several generations, but would disappear from the population were it not for the fact that it is constantly being re-introduced by fresh mutations.  Here is an allele with early benefits and late costs that is being rejected by natural selection on an ongoing basis.  So should Huntington’s be considered a counter-example to the AP theory?

Grade inflation for (some) scientific theories

Nowhere in science are theories given a pass when contradicted so frequently and so flagrantly as in evolutionary theory of the selfish gene.  Manuscripts describing evidence against the selfish gene, or theories based on group selection are routinely rejected for publication.  (This situation isn’t nearly as bad as it was 15 years ago.)  But Antagonistic Pleiotropy continues to get by with a “gentleman’s C”, because (like the Ivy League preppies), the theory has a pedigree.

“Direct experimental evidence for age-specific effects of mutations comes from only a handful of reports” [Scott Pletcher and Jim Curtsinger]  These geneticists actually mutated fruitflies at random and went looking for gene variations that could cause benefits at one stage of life and costs at another.  And they found them!  Except, curiously, they were all at early stages of life, and none affecting old age [ref].  “The main evolutionaty models of senescence are antagonistic pleiotropy and mutation accumulation, neither of which has substantial experimental support.” [1995]  Yes, that was written move than 20 years ago.  The difference today is that we now have a huge body of evidence contradicting each of these theories.

May we live to see the day when scientists look back at the theory of Antagonistic Pleiotropy, scratch their heads and say, “I wonder why people would have believed that!”

AgingAdvice page is back online

Thanks to some of my readers who noticed that had disappeared.  It is now back online. is also back online.

(The site had been hosted by GoogleDrive, and I missed Google’s announcement that they would no longer be supporting public web pages.  The page now has a permanent home at  The web address remains the same.)

Putting the “system” back in Systems Biology

Cold Spring Harbor labs on Long Island has a diverse offering of conferences that attract experts from all areas of biology. For the last six years, there has been a sister group organizing conferences in Suzhou, China. I spent last week at the 2016 CSH Asia conference on Systems Biology.

While I have been to many conferences on aging and a few on evolution, this was my first Systems Biology conference. I looked forward to learning how biologists think about whole-body issues of homeostasis, organization, and (maybe if I was lucky) blood signals that regulate aging.

What I found instead was that researchers in systems biology are doing what other biologists are doing: they are babes in toyland, exploring the potential of a seductive array of new biomolecular tools. They are compiling catalogs and making maps and correlating every chemical they can find with every other chemical, and collaborating with statisticians to look for patterns in the data. If “systems thinking” is from the top down, what I found at this meeting was just the opposite.

A hundred years ago, Lord Rutherford said that “All science is either physics or stamp collecting.” He was mocking the biologists’ program of collecting specimens, classifying and cataloging them. Twentieth century biology turned this around; it was neither physics nor stamp collecting, but model-building. Systems biologists in particular have analyzed living organisms in terms of signals and networks and energy flows, and have generated a great deal of understanding. At its best, biology has forged a new mode of science.

So why is it that 21st Century systems biology is looking once more like stamp collecting? It’s a question I asked one of the conference organizers (in more polite terms), and he responded that “we are working from a reductionist framework. We are trying to build understanding from the bottom up.”

There’s a deeper answer

Why, after the revolutionary successes of late 20th century biology, should bioscience find itself back at square one, trying to build a foundation? The short answer: genetics is simple; epigenetics is complicated.

The heyday of genetics started from Crick’s decoding of the genetic code in 1961. DNA was revealed to be a blueprint for producing proteins that would do the body’s work. The code was just as simple and elegant as it could be, and the machinery to do the translation was segregated in ribosomes, which could be isolated and picked apart. The era of genetics ended in 2003 with the completion of the human genome project. Results were a surprise to everyone, and the message took awhile to filter into conceptual thinking: The genome is 3% genes and 97% gene regulation. All the impressive tasks of development, homeostasis, and metabolism are performed by an exquisitely adapted system that turns genes on and off in the right place at the right time.

2003 ended the era of genetics and began the era of epigenetics. How is gene expression regulated and contolled? DNA methylation was the first mechanism discovered. But as clues appeared and mechanisms were partially elucidated, it has become apparent that epigenetics is as complicated and intractable as it can possibly be. Besides methylation, there are more than 100 modifications of the DNA and its associated proteins (histones) that affect gene expression. There is also the way in which DNA folds around itself, leaving some regions open where they can be transcribed and keeping other regions under tight wraps. Finally, there is a variety of post-translational modifications; even after a stretch of DNA has been transcribed into RNA and translated into a protein, the protein can be turned on or off by adding a phosphate group or a methyl or acetate at any number of receptor sites.

Metabolism is now seen as a dense web of interacting processes, intertwined causes and effects. Gene network maps draw lines between genes that are co-expressed, and can divide the territory into subsets (modules) that are more closely related to each other than to other modules.


But this is a picture that only a computer could love; it contains intricacies on a scale that human consciousness cannot grasp with conceptual understanding.

Contrast this to the naive simplicity of Crick’s Central Dogma of Molecular Biology: Information flows in one direction, from DNA to RNA to proteins. Crick lived to see his insight de-dogmatized by exceptions, but it has been since his death (2004) that the essential, bewildering complexity of biochemical networks has been revealed.

No wonder the community of systems biologists feels that they are starting over again, collecting, classifying and cataloging stamps.

New Tools

Biochemical science this last few years seems to be driven by newly available technologies. These are so powerful and coming so fast that just exploring what they can tell us is occupying the lion’s share of available funding and lab space. I knew about some of these, and several more were new to me last week.

  • CRISPR-Cas9. This is a tool adapted from bacterial defenses against viruses. It has made it easy to delete a particular gene within a living cell culture, and perhaps within a living, breathing animal. It has been adapted to insert an exogenous gene at a particular location on a particular chromosome, and even to modify a particular section of DNA to turn a gene on or off. Cas9 has been limited to small “payloads”, adding short sequences of DNA, but just last year, techniques were reported for splitting a larger payload among multiple Cas9 vectors [Ref1, Ref2] in such a way that they piggyback.
  • Hi-C is a modern, computer-intensive version of a 20-year-old procedure for mapping a coiled and folded chromosome in 3-space. First, the chromosome is frozen by introducing random bonds between nearby strands. Then it is fragmented with a DNA slicing enzyme. Then the pieces are sequenced (this is the new part) with high throughput sequencing that can tell you which genes are physically closer to which other genes in the folded, 3-D configuration.  Finally, the computer can be used to reconstruct a picture of the 3-D configuration.
  • ATAC-Seq. This is a tool for finding the genes that, at any given time, are in open stretches of DNA (euchromatin), available to be transcribed. Chromosomes are peppered with an enzyme that slices up DNA. The fragments are then collected and sequenced, and a computer program matches the fragments to map where they came from. The DNA that was tightly-packed (heterochromatin) contributes few fragments because the enzyme can’t reach it. Thus the genes that are seen are representative of what is available for transcription.
  • Methylation mapping. Methylation of C’s in stretches of C-G-C-G-C-G-C-G-C-G within a chromosome is the best-studied mechanism of epigenetic regulation. Just in the last few years, it is possible to map the methylation state of an entire genome. A chemical transformation transforms only unmethylated C’s to uracil in a strand of DNA (with bisulfite), leaving the methylated C’s unconverted. By sequencing the strand before and after this transformation, and using a computer to map the differences, the places where C’s were methylated can be identified.
  • ChIP-Seq. If you know of a particular transcription factor—a protein that binds to DNA and turns certain genes on or off—then this technique can tell you where on the DNA the protein attaches itself. The technique combines two older technologies: immunoprecipitation, where an antibody is introduced that picks out one particular protein, and high-throughput sequencing, which identifies and locates the patch of DNA that is stuck to the CHIPped protein.

Gene expression maps have been around for a few years. They provide an enormous amount of information about what genes are being expressed where and when, but they are notoriously difficult to make sense of.  More recent are correlation maps, in which every gene is correlated with every other gene in a huge matrix that shows how likely they are to be expressed at the same time. I am intrigued by principal component analysis. You can start with a set of genes and measure all the cross correlations, and the math comes up with a combination of the genes most likely to be expressed together (Principal Component #1).

Sometimes a single gene sticks out, and the authors conclude that this particular cancer can be treated by targeting this particular gene.

More often, the results show a combination of hundreds of genes that tend to be expressed together in a particular proportion, say 1.2% gene #1, 0.04% gene #2, 0.15% gene #3…and so on, with coefficients for hundreds of genes. This is the output of a principal component analysis. If such a profile is identified with a healthy state, or a young state, we do not yet have the capability to shape this profile of gene expression in a cell culture, let alone in a living animal. But it is not inconceivable that we will acquire this ability with advancing biotechnology of the coming decade(s).


The Harvard laboratory of Brenda Andrews is fully automated, with robotic handling of yeast culture plates, robotic data collection, computerized data analysis. All that’s left for the human to do is to write the historical introduction and submit the manuscript. I am a fan of artificial intelligence and computer learning for some applications. Computers have their own ideas of what constitutes a pattern or a trend. They often come up with unexpected solutions to problems, even simple solutions on rare occasions. But AI never produces elegant theories or new ways to look at the big picture. We give that up when we rely on computers to do science for us.

Growth, Development and Aging

Growth and development are programmed, to be sure, but (so far as we know at present) there appears to be no central coordinator of the process. Rather, the tangled web of chemical signals adapts and responds to changes in the body and in itself. The intelligence is not in a central brain, but is distributed through the system itself. There is no one calling the shots. The metabolism behaves intelligently the way a beehive behaves intelligently, though no single bee has a a clue concerning the hive’s plans and strategies.

I have bet my career on the thesis that aging is a metabolic program, a continuation of the process of development into a phase of self-destruction. I used to think that this meant there were genes for aging. I was the most optimistic speaker at the anti-aging meetings. “All we have to do is find the aging genes and turn them off.”

Then I accepted the new picture centered on epigenetics. I thought that chemical signals were arranged in hierarchies, with a few hox genes and transcription factors controlling a much larger number of workhorse proteins that actually get the job done. The job of the anti-aging scientist is to re-balance the transcription factors to create a more youthful profile, and the workhorse proteins would dutifully take care of the rest.

But more recently, I learned that there are thousands of transcription factors, comparable to the number of genes they regulate.  And the lines between promoters, enhancers, transcription factors, and metabolites has been blurred.  A less optimistic scenario is beginning to come into focus for me. I believe that aging is a continuation of the developmental program, but development is inscrutably complex, and it seems to be controlled by a web of interacting molecules that play multiple roles. Each one is a cause and an effect. Many have roles both a regulatory agents and also as workhorses. There’s no one in charge of the factory. The factory is designed so ingeniously that it runs itself.

Study of Development may be a Key to Aging

Much is known about details of development, but there is no systemic understanding of how the process is put together

    • How much is predetermined in cell lineage?
    • How much is self-organization?
    • How much is centrally organized, through internal secretions?
    • How do these three interact?

Of course, the same questions may be asked about aging. It may be more feasible to approach these questions through development than through aging, (1) because development happens on a faster time scale, (2) because aging contains a stochastic element not present in development, and (3) because the phenotypes of development can be observed clearly and locally. I recognize that this suggestion means going back to basic science to make a long-term investment in understanding of aging, but maybe that’s what we need.

Energizer lab worms keep on keeping on long after they have stopped laying eggs

C. elegans worms live up to 3 weeks, and for the last 2½ weeks, they are post-reproductive, unable to lay fertile eggs because they have run out of sperm to fertilize them.  Why do they stop fertilizing their eggs, when sperm is metabolically ‘cheap’? Why has evolution endowed these nematodes with such an extended period of non-productive life?  In mammals, it is common to speak of the “grandmother hypothesis”—that human females live on past menopause in order to have time to take care of their grandchildren.  But worms haven’t been observed to care for their grandchildren.  

My hypothesis is that, nevertheless, maybe they do.  The service they provide to their grandchildren is in the form of pheromones.

Pheromones are powerful chemical signals.  Incredibly small amounts can affect behavior.  Hormones are chemical signals within the body, and pheromones are like external hormones, directed toward the behavior of other individuals.  (When the individuals are of a different species, they are called kairomones.)

C. elegans is the lab worm that has been so useful in lifespan experiments.  In the wild, it is thought that these millimeter-long worms live in the ground on rotting fruit or mushroom.  What is clear is that their life history is exquisitely adapted to boom-and-bust cycles of food availability.  Like many animals, they live a long time when they are waiting for food to appear, and a short time when they are eating and reproducing.  And unique to C. elegans, the worm’s best trick is to go into a state of semi-dormancy, something like a spore, that can live for months at a time without food or water, and which resists heat, cold, chemical toxins and other insults.  The spore-like state is called a dauer.

Young worm — Old worm

Young worm — Old worm

About 18-24 hours after a worm egg hatches, the stage-3 larva makes a decision whether to go for it, grow and eat and lay lots of eggs, or to become a dauer, to wait and bet on a better opportunity later on.  My hypothesis starts with the idea that the dauer state represents the only way that a worm can hope to spread its progeny from one food site to another, which is essential if the lineage is to have a long-term future.  “A chicken is an egg’s idea for making more eggs.” A colony of worms on one food source is a dauer’s way of making more dauers.

Come with me, and explore the dauer’s-eye perspective for a moment.  You are a fraction of a millimeter long, and you weigh a few billionths of a gram.  Imagine that you are carried by a bird or animal or by the wind, and you land on a piece of fruit.  Your lucky day!  Sensing food and moisture, you morph from the dauer state, turn yourself back into a larva, and you eat and eat, you grow and grow, and you lay several hundred eggs, all endowed for life with a copious food supply.

But if you’re thinking for the long term (all right, worms don’t have brains; but your genes can still be thinking) — if you’re thinking for the long term, your strategy will be to produce as many dauers as possible from this one piece of fruit.  Each dauer is a lottery ticket for your future legacy.  Remember that this piece of fruit is finite, and that when it’s gone, life beyond this one oasis is a very chancy proposition.

In the end, a good measure of your success in the evolutionary game—your fitness—is the number of dauers that come out of this piece of fruit.

With dauer number in mind as a goal, what’s your best strategy?  Well, for the first generation, it’s to produce several hundred eggs.  For the second generation, it’s to produce tens of thousands of eggs.  For the third generation, several million eggs.  But at that point (or possibly the fourth generation, depending on survival of your grandchildren) it will be important not to keep going with egg-laying, but to start generating dauers.  The decision that every larva must make should, for optimal fitness, be NOW for the first generation, NOW for the second, NOW, for the third, and LATER for the fourth generation.

But how are you to know that it’s the fourth generation?  Remember that you haven’t got eyes or ears or a brain.  You might just keep choosing NOW while there’s food, and wait until there’s no more food to say LATER.  This would be something you can sense for yourself, but (crucially) this is a flawed strategy.  The problem is that your population is growing exponentially.  Exponential population shoots up so quickly that there is no warning at the end.  There might be a billion larvae all competing for the food that was perfectly adequate for the last generation, when the population was a hundred times smaller, but now there are so many mouths to feed that NONE of them will make it to Stage 3 Larvahood, when the worm is mature enough to become a dauer.  

The population that can sense crowding and decide LATER before there is a food shortage has a big advantage in the number of dauers that will eventually be produced.  This is where your grandmother can be of great assistance.  She has stuck around, though she’s all done laying eggs, and has no prospects for herself, but she and her children can send pheromone signals to their grandchildren, warning them, “Don’t do it!  Don’t grow up!  Take refuge in dauerhood while there’s still time.  If you wait until we run out of food, it will certainly be too late!”

My theory is that the reason that C. elegans goes on living so many days beyond its fertility is that she is sticking around to send pheromone signals to her great grandchildren.  The 2-3 week lifespan is just sufficient to last through 4 generations.  The theory makes predictions that are being tested in the Beijing lab of Meng-qiu Dong, where I am a visiting scholar this fall.  Predictions are

  1. Life span should be extended in the presence of many old worms.
  2. The presence of just a few very old worms should be sufficient to bias a young larva’s decision toward becoming a dauer.
  3. Dauers should be hardy enough to survive the digestive tract of a mouse or bird, so that they can hitch a ride out into the wide world, looking for a new food source.

Nictation movie

Here’s a 6-second movie of nictating behavior in a dauer of C japonica, a cousin of C. elegans.  Does the dauer look like she’s hiding from predators, or does it look like she’s begging to be eaten?  My guess is that worms depend on larger animals to reach new food sources that they could never find in a lifetime at their usual squirming pace in the ground.

Prediction (1) has already been tested in the Dong lab, with encouraging results.  But the other two are stronger consequences of the theory, and I’ll be eager to see how the experiments fare.

Note on evolutionary theory and the state of the science

George Williams laid the foundation for the evolutionary theory of aging that is widely accepted and applied today.  In his seminal paper of 1957, he was bold and astute enough to make 8 predictions that could be used to validate (or falsify) his theory.  In the intervening years, only 2 of the 8 have been borne out, and 4 have been flat-out falsified.  One of the predictions that turned out to be false was that death ought to ensue promptly when the capacity for reproduction is lost.  Reproductive lifespan and actuarial lifespan should coincide closely, but they don’t.

Williams was, of course, aware that human females are an exception, handily explained by the “grandmother hypothesis” — older women are motivated to stick around because rearing young humans takes such a long time that a woman really needs to outlive her fertility.  But he would be surprised to learn that chickens and whales, partridge and elephants, guppies and yeast cells all have substantial post-reproductive lifespans.

It is to Williams’s credit that he put out a well-reasoned theory and volunteered ways it could be put to the test.  On the other hand, it reflects badly on the evolutionary scientists who came after him that as the theory was falsified time and again, they clung to the theory, patched it, made excuses for it, but never put it aside to look for a theory that aligns better with experimental reality.

With a lifespan eight times as long as their fertile life, C. elegans worms are in a class by themselves.  Their post-reproductive life has been recognized as a scientific puzzle, and I look forward to finding out if my own theory will stand up to experimental tests.

Nutritional Geometry 3: Ketosis— benefits & risks of oil-rich diets

The advantage of a low-carb diet is that it minimizes insulin spikes that can contribute to loss of insulin sensitivity=metabolic syndrome. The advantage of a low-protein diet is that it offers some of the anti-aging benefits of calorie restriction, and is associated with lower all-cause mortality. Can the two be combined? The low-protein, low-carb diet is by definition a high-fat diet. High fat diets are terrible for mice, but maybe they’re good for people. For more than a century, many people have found a high-fat diet is a path toward weight loss. Just in the last few years, there is a lot of salesmanship based on a little science that suggests a ketogenic diet can be healthy for the brain.

Does a high-fat diet induce ketosis? Is it practical? Is there a price to pay for too much oil?

This blog edition also features a description of my personal eating habits, as a curious example rather than a universal prescription.

There are but three macronutrient classes, so the only way to have a low-protein, low-carb diet is to eat a lot of fats. The low-carb diet has at least a 150-year history.

One of the first registries on low-carbohydrate diets was in 1860 when English casket maker William Banting was prompted to lose weight and decided to write “Letter on Corpulence, Addressed to the Public”, which aimed to completely avoid starch and sugar. Banting lost 45 pounds in a few weeks (with additional weight loss over several months) on a diet composed by meat (generally mutton or beef – plus poultry and fish), two very small (1 ounce) portions a day of rusk or dry toast, tea (with no sugar or milk), and a 2-4 drinks of dry wine or port a day as spelled out in his own writings. Thus, the Banting diet became a very well known method during that period of the 19th century, promoted also for weight loss and diabetes control [Wikipedia].

Diets comprising 80-90% fat have a remarkable benefit for people who suffer epileptic seizures. Known generically as ketogenic diets, they have been recommended by extension for other neurological disorders, and, of course, for diabetes (types 1 and 2). There is some evidence that low-carb diets protect against Alzheimer’s Disease. When sugar is not available, the body turns to fat as a fuel, and converts fat to three related biochemical forms (called ketone bodies) as a circulating intermediary. Cancer cells, however, can’t use ketones, so cancer also responds to a ketogenic diet (and even better to fasting). But if you don’t have a life-threatening disease and you don’t happen to be an Inuit, a diet that is 80% fat may feel extreme. It takes a lot of motivation to stick to a ketogenic diet, and for people who are basically well, the promised benefits are not commensurate with the discipline. All of the evidence for benefit in healthy individuals is theoretical, based on biochemistry.

Studies of lab mice consistently show that a high fat diet leads to shorter life span, compared to carb- or protein-based diets. The reason for this seems to be that fat nurtures a kind of intestinal flora that excite an immune response called endotoxicity. It’s the elevated inflammation that shortens lifespan. Whether this response is essential to high-fat diets or whether it is exacerbated by refined carbohydrates in the mouse chow, whether endotoxicity is also induced in humans on a high-fat diet–all these subjects are vigorously debated. The one clear message is that fiber is an antidote, so that anyone considering a high-fat diet should be doubling up on dietary fiber.


A Tasty, Satisfying Fat-based Vegan Diet

Think avocado salads and fried green vegetables with a bit of tofu. Think coconut and walnuts and greens and more greens. Here are some recipes from the incomparable Enid Kassner. All are guaranteed delicious, and all have 70-75% of calories from fat, with the residual comprising various mixtures of carb and protein.

1. Saag Tofu

8 oz spinach (washed and roughly chopped)
5 oz fresh tomato, chopped
6 oz extra firm tofu
1.5 oz coconut oil (3T)
Grated fresh ginger, chopped garlic, garam masala
(Indian spice mixture)
Press extra liquid from tofu using a towel. Cut into cubes, sprinkle with salt, and microwave about 3-4 minutes. Set aside. Heat oil and add ginger, garlic, and spinach. Stir frequently as spinach cooks and reduces in volume. Add chopped tomato and cook lightly, adding tofu, salt and garam masala to taste.


2. Fried Cauliflower with Tofu and Cashews

9 oz cauliflower florets
2.5 oz sweet red pepper, sliced
2T + 1t peanut oil
Scant oz chopped roasted cashews
4 oz extra firm tofu

Press extra liquid from tofu using a towel. Cut into cubes, sprinkle with salt, and microwave about 3-4 minutes. Set aside.

Heat oil and cook vegetables, stirring frequently, adding garlilc, if desired. Add tofu and nuts, salting to taste.


3. Marinated Vegetables

5.5 oz mushrooms, cleaned and sliced
3 oz chopped cucumber
4 oz green beans, chopped and lightly boiled (about 3-4 minutes)
.5 oz finely chopped sweet onion
2 oz sliced black olives
1.25 oz toasted almonds, sliced or chopped
1.5 oz olive oil (3T)
1 oz vinegar (2T)

Combine olives and vegetables and marinate in oil and vinegar, adding salt and pepper to taste. Can also add dried herbs, such as oregano, basil, or thyme. Let sit several hours at room temperature or overnight in refrigerator. Sprinkle with nuts when ready to eat.

A Bit of Biochem

Ketones are carbon chain molecules with an oxygen double-bonded to a carbon (C=O) somewhere in the middle. Beta hydroxybutyrate (BHB) is best-known of three “ketone bodies” that circulate in the blood. It is burned as fuel, but it is also a signal molecule “BHB has been found to act as a histone deacetylase (HDAC) inhibitor and to increase brain-derived neurotrophic factor (BNDF) levels and TrkB signaling in the hippocampus.” [ref] (BHB signals growth of new neurons and affects gene expression in unknown, complex but probably good ways, since BHB is associated with fasting and exercise.)

When the body burns ketones instead of glucose, less oxygen is needed. Theoretically, in intense aerobic exercise, when the body is limited by how fast oxygen can be pumped through the lungs and into the blood, there ought to be a slight benefit in power when the body is in ketosis mode. One wonky self-experimenter working with the lab of Dominic D’Agostino at U of S Florida claims to have measured and confirmed this effect in himself.


Eat Ketones?

If much of the benefit of a low-carb diet comes from the body’s adaptation via ketosis, why not cut out the middleman and just eat ketones? Once again, the miracle of capitalism has advanced ahead of the plodding pace of epidemiological science. There are several products to choose from. Raspberry ketones seem to be worthless. Ketones are cheap to manufacture, but you need a large quantity because it’s a food, not a supplement, and ketones taste awful. (Why should sugar taste so good when it’s so bad for us, and why should ketones taste so bad? Maybe because evolution is keenly concerned with our short-term survival, but is ambivalent about prolonging our lives.) Medium-chain triglycerides as found in coconut oil and butter seem to be a platable way to boost the benefits of a ketogenic diet, including weigh loss.

D’Agostino is researching and developing palatable ketone supplements.

This summer, Andrew Murray and colleagues at Oxford University reported an experiment in which mice had a ketone supplement (not BHB) added to their chow, and they showed both faster learning and greater aerobic capacity [pre-pub ref].


Modified Atkins Diet

Dom D’Agostino is the king of ketogenic research, and for himself he has chosen a Modified Atkins Diet accompanied by ketogenic substitutes, which offers much of the same benefit as a ketogenic diet. The original Atkins diet was heavy on meat and fish. The Modified Atkins Diet developed at Johns Hopkins for epilepsy has less protein, 65% fat and ultra-low carbohydrates (~5%) but more flexible than the ketogenic diet.

There are a range of generic Atkins diet spinoffs, including some that have less or zero meat. (I keep coming back to vegetarian options not just because my inclination is in this direction, but because there is good evidence for a longevity benefit. I also respect that other bodies make other choices.) All the “modified” versions introduce a lot more green vegetables, because their fiber and nutrients add a lot of value, and because the diet is much more varied and platable with vegetables. Some Atkins versions allow limited fruit. Atkins-spinoff diets tends to have less protein than the original and 50-60% fat, with limited carbohydrates, but more than the strict 5% prescribed for epilepsy by the Hopkins docs.


My diet

People ask how I eat, and I’m happy to tell them, but I make clear this is not a recommendation. Diets are personalized. At one level, there’s what you can live with and feels good to you; at a deeper level, you can experiment with different diets, see how your weight and your energy level and your emotional and intellectual life respond; at a deeper level yet, sensitize yourself to your body’s signals with yoga or biofeedback or meditation techniques, and perhaps your body will let you know what it wants.

Fresh vegetables, fruits, nuts, soy and other beans are the mainstay of what I live on. In addition to fat from nuts, I dress salads generously and stir-fry my vegetables in oil. I have been vegetarian since 1973. Lately, my diet is close to vegan, ultra-high fiber, low carb, relatively high in protein. (No vegetarian diet can be high-protein by Atkins standards.) Fish oil capsules are my one departure from strict vegetarianism. I start the day with a big bowl of raw wheat bran (the only wheat that I eat), made palatable with fruit and soymilk, sometimes blended in a smoothie.

(I’m 67 and exercise frequently and in diverse ways. If I were younger or less active, I would eat less protein.)

I eat no grains or potatoes: no rice, wheat, pastries, pasta, or cereals. Other starches occasionally: carrots, winter squash, beets, parsnips. I eat fruit liberally. I will also occasionally savor a square of chocolate or a spoonful of ice cream as a special treat. I’ll stop what I’m doing and roll it around in my mouth, extending and savoring the experience. An absolute proscription of grains helps me say no to cookies and cakes.

I confine eating to 12 hours each day. I fast one day a week, about 32 hours from Wed evening to Friday morning. I do longer fasts 2 or 3 times a year, and Longo semi-fasts another 4 or 5 times a year.

While I’m in personal mode, I’ll add a note on flatulence. What about all that fiber and beans? The truth is that I’ve had a gassy metabolism my entire life, especially so when I was growing up on a typical American diet of meat-and-potatoes, milk and cookies. In the last 10 years, my body has made a transition to a less prodigious level of flatulence, and I don’t know why–but this has been despite the beans and the wheat bran. (I still can’t eat black turtle beans, though I’d like to.)


The Bototm Line (concluding three long blogs on nutrition)

If we are what we eat, maybe the surprising thing is that what we eat makes so little difference that it requires human studies with tens of thousands of participants to be able to detect an effect of diet on lifespan. Monarch caterpillars eat only milkweed. Pandas won’t eat anything but bamboo. There are hundreds of species of wasp, each co-evolved to drink nectar from only a single species of fig flower. But we humans are omnivores, and our bodies are geniuses of homeostasis, able to stay pretty well on track no matter what we put into them. The differences in epidemiological studies amount to a few percent of lifespan, even as test diets are varied all over the map. Native Americans of the Paiute tribe eat grasshoppers, and Inuits eat blubber; on the Trobriand Islands they eat yams, Amazon tribes eat fruit, while the Masai eat a mixture of ox blood and milk. Yet the similarities in their life trajectories overwhelm the differences.

Nutritional Geometry 2: Carb Restriction

Last week’s focus was the evidence in favor of a low-protein diet.  In this context, high-carb diets came out on top.  But there is also evidence that for the average denizen of the developed world who does not restrict protein, there are dangers in a diet based on staple carbohydrates, especially sugars and simple starches that pass quickly from the stomach to raise blood sugar.

Beginning in the 1970s, health literature convinced Americans to avoid fatty foods, and the processed food industry was eager to oblige, advertising “low fat”, while adding more sugar to make foods tasty, and taking advantage of a new, efficient chemical process that made high-fructose corn syrup cheaper than sugar.  But as we substituted carbs for fat, we became obese and diabetic.  Metabolic syndrome and Type 2 diabetes were new terms added to the medical lexicon to describe what was ailing us.  Gary Taubes was first to hypothesize a causal relationship:  Our high-carb diet was leading to insulin resistance (which promotes weight gain) and weight gain (which promotes insulin resistance)—a vicious cycle that he first wrote about in the 1990s.

  • Diets that are high in fat, low in carbs, are an effective way to lose weight, at least in the short term.  Herman Taller, Robert Atkins, and Barry Sears taught this truth to three successive generations of Americans.
  • In animal experiments, insulin and its cousin IGF-1 are the hormones that mediate the connection between more food and shorter life.
  • Blood sugar levels rise with age, and in people with genes for exceptional longevity, the rise happens more slowly.  Blood sugar levels are a risk factor for mortality.  So how much of a stretch is it, really, to say that the rise in blood sugar with age contributes to risk for the diseases of old age?


The case against carbohydrates comes right out of mainstream practice for diabetes, but it has also been treated as a fringe fad when David Perlmutter stretched the case to make a point in a series of bestselling books.  In Grain Brain, Perlmutter pounds home the association between high blood sugar and all the diseases of old age, but most especially dementia.  (Vascular dementia to a greater extent than Alzheimer’s disease.)

The combination of biochemistry with population data associating carb intake with metabolic syndrome has convinced many people that a carbohydrate-based diet is a hazzard.  But it’s a difficult case to prove, because humans don’t take well to living in cages, and because epidemiological studies of human aging require decades.  In reading this week, I’ve discovered just how contentious is the whole subject of low-carb vs low-fat diets. Many such deeply divisive questions about health can be traced to corporate interests on one side, but this one may be academic, with ambiguous data, no long-term results, and different individual responses that are seen through different theoretical lenses.

Although bottom-line questions about mortality and life expectancy may be difficult to address in human studies, we might hope for an answer to the question: Do people whose diets have a lower glycemic index have a lower risk of metabolic syndrome?  The best study I’ve been able to find on this question [2004] associates insulin resistance with dietary factors in 2,800 sons and daughters of the original Framingham heart study.

After adjustment for potential confounding variables, intakes of total dietary fiber, cereal fiber, fruit fiber, and whole grains were inversely associated, whereas glycemic index and glycemic load were positively associated with [insulin resistance]. The prevalence of metabolic syndrome was significantly lower among those in the highest quintile of cereal fiber and whole-grain intakes relative to those in the lowest quintile category after adjustment for confounding lifestyle and dietary factors. Conversely, the prevalence of metabolic syndrome was significantly higher among individuals in the highest relative to the lowest quintile category of glycemic index.

Fruits and whole grains were found to provide protection against insulin resistance, despite the fact that they are primary carb sources.  Presumably, it is only sugar and simple carbs (white flour, rice, potatoes) that add to risk of insulin resistance.

A South African doctor collected stories from patients who, by and large, were very satisfied with the results of switching to a low-carb, high-fat diet. Almost all lost weight.  Some claimed that their diabetes was “cured”.

In this study, people lost weight on a six-month program of either restricted fat or restricted carbs.  But people who were already insulin-resistant did a little better on the low carb diet, while those who still retained insulin sensitivity lost more on the low fat diet.

This study put obese subjects with metabolic syndrome on either a low-fat or low-carb diet for six months.  Both groups lost weight and gained insulin sensitivity, on average.  The low-carb group lost more weight and gained more insulin sensitivity.  However, there was a lot of variation within the groups.

Insulin resistance is associated with diabetes and heart disease, both independently and as part of metabolic syndrome. Exercise has a strong beneficial effect and obesity a strong adverse effect. The balance of evidence suggests that a high-fat diet is likely to reduce insulin sensitivity but the effects of dietary carbohydrates are more controversial. Extensive studies in animals showed a detrimental effect of diets very high in fructose or sucrose, particularly in association with induction of hypertriglyceridemia. The more limited studies in humans had conflicting results, partly because of heterogeneity of design. Certain groups of subjects may be more sensitive to adverse effects of high intakes of dietary sucrose or fructose. [ref]

In other words, “There is conflicting evidence concerning the influence of total carbohydrate intake on insulin sensitivity.”

Two NIH studies [one, two] by Kevin Hall just this year compared short-term effects on metabolism from carb and fat restriction.  They put people in metabolic chambers to measure CO2 and H2O in their respiration, in order to calculate how much fat was being burned.  Hall claims that the results disprove the insulin theory of weight loss.  But to me the results seem puzzling and inconclusive.  They claim to calculate that the short-term weight loss from carb restriction is loss of muscle, not fat.  This is disturbing, if true.  The metabolic calculations are based on isotope labeling and other sophisticated technologies.  I trust the chemistry, but I tend to skepticism based on the fact that once in the body, labeled water gets mixed to an unknown extent with ubiquitous body water.  Short-term studies with sophisticated metabolomic measurements might tell us a good deal about the body’s biochemistry, but still leave us wondering about long-term accommodations of hormonal balance, energy metabolism, and gut biota.

Past positive results from low-carb diets, Hall says, are probably about “compliance” and not metabolism.  “Compliance” is our ability to stick with a diet, and, IMHO, this should not be separated out as some kind of soft, psychological confounder.  It may well be that the whole advantage of a high fat diet is that those people for whom it works—not everyone—feel less hunger and more sustained energy, and that may well be linked to insulin cycling.

What can we conclude but that we’re each on our own, and we have to find the diet that works best for us as individuals?  And that that our dietary needs may change with age, so repeating the self-experimentation at least once a decade is helpful.  In experimenting on yourself, keeping weight off is probably as good a measure as any of how well your body is responding.
Glycemic index and glycemic load

Glycemic index is about how quickly the carbohydrates in a particular food enter the bloodstream.  Glycemic load also takes into account how much carbohydrate the food contains, and also a guess at portion size.  Here’s a chart from Harvard Med School with glycemic index and glycemic loads for 100 “common foods” (some more common than others).  Much of the chart is predictable—cakes and sodas look bad, beans and nuts look good.  There are a few good surprises, and a few bad ones.  (Note that the GL listed for oranges =45 is almost certainly a mistake.  It should be 5 or 6.)

Good Surprises         GL Bad Surprises              GL
Premium Ice Cream 3 Cornflakes 20
Watermelon 4 Ocean Spray Cranberry Juice 24`
Apple 4 Pasta 26
Peanut M&Ms 7 Raisins 28
Whole Wheat bread 8 Baked potato 33
Regular ice cream 9

The ranking by glycemic load is appropriate if you are trying to minimize total insulin burden.  But if you are aiming for a low-protein, high-carb diet as described last week, then you are interested in glycemic index (because you want high-carb foods that don’t trigger insulin release).  The catch (for protein restricters) is that most foods with low GI are protein sources.  Which foods offer a combination of low protein and high carb without the insulin trigger?  Grapefruit stands out, apples, pears and other fruits will be preferred carb sources.  Some kinds of brown rice are more equal than others, while potatoes will be avoided because of too high a GI, while whole wheat and corn will be taken in moderation because they have too much protein.


Fructose, Glucose, Sucrose

So lotsa fruit seems to be the answer…until we introduce one more wrinkle.  Fruit contains fructose, and there is a school of thought that says fructose is much worse for you than glucose.

There are two simple 6-carbon sugars, fructose and glucose, and table sugar=sucrose is a loose binding of one fructose with one glucose.

Fructose and glucose are both sweet, and they’re often found together in fruits.  Apples and pears have a lot more fructose than glucose, while bananas, peaches and sweet potatoes have a little more glucose than fructose.  Honey has more fructose than table sugar.

Starch is a polymer of glucose.  It is quickly broken down (beginning in the mouth) into glucose molecules, so starchy foods have a high glycemic index.  But starch is all glucose, no fructose.


Glucose and fructose may be chemical cousins, but the body treats them quite differently in the short term.

  • Glucose is fuel, usable right away.  When you eat enough for your activity level, glucose is absorbed right into the blood, and it is consumed promptly.  When you eat more glucose than you can burn, insulin is secreted, signaling the liver to remove some glucose and turn it to glycogen.  The liver stores about a day’s supply of glycogen to be drawn on as necessary, and glucose in excess of that is turned to triglycerides, a form convenient for storing energy in fat cells.
  • Fructose is also absorbed promptly from the stomach into the bloodstream, but it is removed immediately by the liver, turned directly to triglycerides.  No insulin is involved.

The short-term metabolism of fructose and glucose is well characterized, but you and I are interested in the long-term consequences of eating fruits high in fructose compared to starches which are quickly metabolized to glucose.  This turns out to be a controversial topic.

In recent years, Robert Lustig and Richard Johnson have argued that foods with more fructose than glucose lead quickly to insulin resistance.  They blame soaring rates of obesity and metabolic syndrome=type 2 diabetes on the invention of a process for producing sugar from corn starch that is cheaper than cane sugar.  The “high-fructose corn syrup” that results happens to be 55% fructose.

Yes, fructose has a low glycaemic index of 19, because it doesn’t increase blood glucose. It’s fructose, for goodness sake. It increases blood fructose, which is way worse. Fructose causes seven times as much cell damage as does glucose, because it binds to cellular proteins seven times faster; and it releases 100 times the number of oxygen radicals (such as hydrogen peroxide, which kills everything in sight). Indeed, a 20oz soda results in a serum fructose concentration of six micromolar, enough to do major arterial and pancreatic damage. Glycaemic index is a canard; and fructose makes it so. Because fructose’s poisonous effects have nothing to do with glycaemic index; they are beyond glycaemic index. [Lustig writing in The Guardian]

I’m not so impressed with the “seven times faster”, because fructose doesn’t remain long in the bloodstream, and I’m not so concerned about free radicals because (as I’ve written) they are as likely to increase our life expectancy as to decrease it.  Lustig also writes that because fructose tastes so good and bypasses insulin and blood sugar, it undermines the satiety response and leads to compulsive eating.  But the most complelling claim here is about the loss of insulin sensitivity, which I regard as a hallmark of aging.  Is fructose really worse for insulin resistance than glucose?  Lustig says YES, and his theory is articulated here.  Lustig makes his case by reasoning about biochemistry in the liver.  But what about real evidence in real people?  In short-term studies, substitution of fructose for glucose in the diet shows no sign of increasing insulin resistance; on the other hand, there is a well-known correlation between consumption of high-fructose corn syrup with metabolic disease.

What Lustig comes to beneath the headlines is, “the dose makes the poison”; and I think this is a healthy attitude for all of us.  Drinking sugared beverages and eating (more than occasionally) foods sweetened with high-fructose corn syrup damages insulin sensitivity.  At the other end, eating a few pieces of fruit during the day can be part of many diet plans that work well for health and longevity.  Those are the easy cases.  In between we have the more difficult case of the semi-fructarian.  That would be me.  I get most of my carbs from fruit, and I avoid starch (rice, potatoes, bread, pasta).  I maintain weight with exercise and portion control, I eat leafy greens every day and I get a ton of fiber, and though my protein intake is high compared to last week’s ideal (~60g/day), it’s all vegetable protein.  Would I be better off if I backed off from my fruit consumption and substituted whole wheat bread and other complex carbohydrates?  It’s an experiment that I might try next winter—but not in September when every kind of delicious fruit is fresh and abundant.

In any case, there is a consensus view that moderate fructose is part of a healthy diet, and that excessive fructose exacerbates the ill effects of a sugary diet [ref, ref, ref, ref, ref, ref, ref].  After reading all these articles (well…reading all the abstracts and some of the content underneath), I’m not convinced one way or the other about fruits (glucose+fructose) vs grains (glucose only, from starch).


Insulin resistance is tied to high blood sugar

Metabolic syndrome, including the “normal” version that comes with aging, is characterized by failure to respond to insulin, leading to both higher insulin levels and higher blood sugar.  Is it the higher insulin level or the higher blood sugar that is responsible for the damage?  YES.

Insulin signaling speeds up the rate of aging.  Sugar in the blood reacts with proteins to create cross links (glycation) that prevents the protein from folding properly.  (Fructose is more prone to this reaction than glucose, but fructose does not stay in the blood so long.)  Type I diabetics have no insulin, and if their insulin injections are not carefully regulated, they are at risk for blindness and nerve damage in the extremities, both from high blood sugar.  So, with metabolic syndrome, both the insulin levels and high blood sugar pose risks.  The proper medical terminology for this situation is “double whammy”.

So both high insulin and high blood sugar are bad for us.  With the separation of fructose from glucose, we have the possibility of coupling lower insulin levels with higher blood sugar. Is the tradeoff worthwhile? Is fructose the optimal low glycemic index sweetener?

And in the end…

You have every right to ask where I’m going to come down on these questions after a post that is longer and fuller of ambiguities than the usual.  I’m going to disappoint you. It’s clear to me

  • that excessive sugar, both glucose and fructose, is bad for most everyone
  • that high fiber is good in a lot of ways
  • that different metabolisms respond differently to low-carb and low-fat diets.
  • that weight control is a good way to tell if a diet is working for you

It leaves me counseling personal experimentation, which is what I always say anyway.

There is a phenomenal amount of individual variability in energy expenditure, both resting and total.   Measured across two weeks, one person had total EE  almost 800 cal/day above their baseline while another had a EE almost 1200 cal/day below baseline.  That’s huge.  I imagine that the individual whose resting EE declined by almost 500 cal/day will be having a tougher time maintaining his/her weight loss than those lucky few who saw increases. [from a pro-carb blogger]


A simple program for weight loss and life extension

Before each time that you eat, do 1 to 2 minutes of exercise, intense enough to leave you panting and drink a pint of water.  The result is to suppress the sugar and insulin spikes that follow a meal, and to burn more of the food energy, store less as fat.

Next week, part 3: Specifics on the high-fat, ketogenic diet

Nutritional Geometry

We all know that the less we eat, the longer we live, and that periods of fasting, long and short, can also trigger a longevity dividend. What about macronutrient proportionsprotein, carbohydrates, and fat? The argument for carb restriction is that it helps keep insulin signaling down, and slows the inevitable advance of metabolic syndrome. The argument for protein restriction is that animals on protein restricted diets have sometimes been found to live longer, independent of total calorie intake. The argument for fat restriction is that mice on a high-fat diet have shortened lifespans compared to either high-carb or high-protein. So, what macronutrient proportions are best for people, or does it matter at all? I have advocated the carb restriction diet in the past, but today I’m considering the evidence for protein restriction, and speculating on the possibility we might be able to do both.

Nutritional Geometry is a 9-year-old Australian approach to macronutrient proportions which has been honing its message more recently [ref, ref, ref]. The topic has provided fodder for research grants (and for bloggers) because it is rich with nuance and resists generalization.

If you are looking for bottom-line advice, I’d say:

  • High-fluid, high fiber content are consistent recommendationsno tradeoffs, no qualifications. Leafy greens rule!
  • Low-protein when you’re young, higher protein when you’re old
  • Vegetable protein is preferable to meat or dairy
  • If you’re game to try something new, a high-fat ketogenic diet may offer advantages.

But the subtleties are interesting and worth exploring, and (as always) the best diet for you is the one you can live with.

Last year, the Australian group published a study in which they fed mice on 25 different diets, differing in protein, fat, carbohydrate, and energy density. The main result from this study is that mice fed a low protein, high carb diet lived longest, though they ate more food—presumably because they sensed that they were not getting enough protein. At the lowest protein concentrations, their total protein was still low, even though they ate more food, and they lived longer, even though they ate more food. For mice, a low-protein chow led to more eating and a longer life. The trick worked for low protein, high carb diets but not for low protein, high fat diets. In this case, the mice ate so much more food that they became obese and their lifespans were shorter. The optimum diet for female mice had an 11:1 ratio of carbohydrate to protein, and for male mice, 13:1.

If we extrapolate to humans, the message would be that for people who prefer not to restrict their portions, a very low protein diet provides a path to a longer life. But this is a dubious extrapolation. The mice were given no choice of chow. (There were 25 different formulations, but only one available to each cage of mice.)  People, in contrast, have a dizzying choice of foods. I know the feeling of having had my fill of fruit, and though not feeling really hungry, craving protein nevertheless. Humans are not at all comparable to lab mice in this regard.

A balanced diet?

A balanced diet?

I wonder for how many people a diet restricted to foods that have carb:protein ~ 12 to 1 is realistic. Here is a list of foods with carb:protein ratios [from USDA web site]:

protein2carb-ratiosConclusion: To get the low protein diet of the mouse experiment, you’d probably have to be a fructarian.

I was surprised to see that the study reported no benefit from a high-fiber diet.

Reduction in calorie intake was achieved by diluting the food with nondigestible cellulose, which allows ad libitum feeding but restricts total energy intake when compensation for dilution by increasing food intake is incomplete. Mice fed experimental diets containing 50% nondigestible cellulose ate a greater bulk of food (3.6 vs 2.5 g/day) but ingested about 30% less total energy than mice provided with food containing higher energy content (30 vs 42 kJ/day). Therefore, these mice had a reduction in energy intake similar to those reported in nearly all other studies of calorie restriction in which access to food was restricted… When corrected for lean body mass, the hazard ratio for death was not influenced by calorie intake, except at the highest energy intakes, which were achieved only by low-protein, high-fat diets.

Fiber in the chow filled the mice up, causing them to eat less calories (though more bulk) than they would have otherwise. But did they live longer? Yes, they did, though you might not get it from the language used here. Lifespan was not increased by lower calories “when corrected for lean body mass”, but whem mice are on a lifelong low-calorie diet, they don’t grow as large, so their lean body mass is smaller. Correction “for lean body mass” is generally not the way data is reported in these experiments. So the result here is not necessarily inconsistent with the great body of experimental results that say lifelong caloric restriction leads to longer lifespan.

Most interesting is the last caveat: The problem with high fat diets is that mice overeat, become obese and have shortened lifespans. But with both high fiber and high fat, the mice tended not to overeat, and their lifespans were enhanced.

This may suggest a practical diet strategy for humans. Mice on a high-fat diet ate a lot more calories, and similarly some people find deep fried foods and milk shakes tempt them to eat too much. But for those with the willpower to interrupt a high-fat meal, they may find that they don’t get hungry for several hours afterward. This is because fat is slower to be digested than either protein or (especially) carb. High-carb meals lead to a fast rise in blood sugar, then an insulin spike that makes blood sugar plummet, triggering hunger. After a high-fat meal, hunger is much slower to return.

High-fat meals lead mice to obesity and short lifespans because they overeat. Extra fiber in the food helps them to regulate their intake. If this works for humans, there is the possibility that a high-fat, high-fiber diet can offer the advantages of both protein restriction and low insulin. I’ll go into this option in depth next week.
Protein: How low can you go?

The biggest issue is maintaining muscle mass, which is crucial to vitality and wellbeing, and becomes a protective factor from mortality as we get older. We have all seen pictures of starving African children with bloated bellies. They are not actually suffering from insufficient calories, but insufficient protein. Their largest muscle, in the abdomen, has beeen deprived of protein so long it has lost all its tone.

Both Pederson and Rand (2013) recommend about 0.85g protein for each Kg of body weight. For a 160-pound man that’s 61g, and for a 125-pound woman, 47g of protein daily. Pederson found that all the diseases of old age are statistically associated with higher protein intake. More general sources quote a slightly lower 0.8g/Kg.

These numbers are only an average over many populations in many studies. Your body might need a lot more or a lot less protein than this, and your best indication is to monitor your energy level, your weight, your muscle mass, and blood analysis as you experiment with different diets.

In this study [2007] of Swedish women 30-49, those in the highest decile of protein consumption died at a rate 20% higher than those with the lowest decile. But mortality rates are low through that age range, and what is more important is the effect on health and mortality in the long term.


Animal vs vegetable protein

In a literature review, Pederson (2013) found links between animal protein intake and various mortality factors, but vegetable protein was either beneficial or neutral. Surprisingly, it is the high-protein diets that are associated with type-2 diabetes, not the high-carb diets. But this conclusion seems limited to animal sources.

This study [2012] from Harvard School of Public Health found a 13% increase in mortality for every daily meal at which red meat was consumed, rising to 20% for processed meats, corresponding to 2 to 3 years of extra life.

Seventh Day Adventists are, as a group, health- and diet-conscious, and they live longer. Their religion tells them not to eat meat, but many do anyway. Seventh Day Adventists who are vegetarian live 3 years longer than Seventh Day Adventists who eat meat.

How does the body know animal from vegetable protein? I have seen no theories on this. Animal protein is generally higher in methionine, but methionine restriction only lowers mortality when methionine intake is very low–probably not the case generally in any of these studies. It could be the saturated fat that accompanies the protein; or it could be hormones that are present in all animals, with higher levels in commercial meat; or it could be an effect mediated through the effect on intestinal flora. But my best guess is that it has to do with heightened inflammation from a low-level immune response to chronic exposure to alien animal proteins.


More protein as you get older

My favorite authority on this and other questions of diet is Valter Longo and his group at University of Southern California. In their 2014 review, they found a dividing line at age 65. Younger than 65, higher protein intake was associated with higher mortality, and older than 65, higher protein intake was associated with lower mortality. As in other studies, the damage was only visible for animal protein, and disappeared into the noise for vegetable protein.

Frailty is an issue in older adults., and greater muscle mass can support a more vigorous exercise regimen. This is a plausible reason for the increased protein need with advanced age. Longo also talks about IGF-1 signaling. IGF stands for “insulin-like growth factor”, and it is a hormone we need when we are young, but which increases mortality when we are older. Lower protein is associated with lower IGF-1, though the statistical association falls short of suggesting that this is the reason that low protein is beneficial.

This is the best article I have found on the subject of increasing protein need with age, but still it is not really what I’d like to see. Mortality in young people is not the best measure of whether a low protein diet is beneficial, because mortality in young people is still low, and even a temporary doubling of mortality make little difference. What we really want to know is how protein in the diet of young people affects their life expectancy when they get older. This is a study that has not yet been done, probably because it involves following a large population for a long period of time (like the Framingham Heart Study and the Whitehall Study in Britain, but these did not address protein.)
Roughage = Dietary Fiber

Everyone agrees that fiber in the diet has a large benefit for gut health and especially for preventing colorectal cancer. I have speculated that the benefit goes beyond this. A high-fiber diet is a calorie restriction program in itself. Fill your belly with fiber, and it you feel full with fewer calories. An ultra-high fiber diet pushes food through your digestive tract faster, so you absorb less of it. Fat is adsorbed on the fiber, and less of it makes it into your metabolism. High fiber in the gut encourages a microbial ecology that affords you less calories.

I speculate based on personal experience, but there is also some literature touching on the subject [ref, ref, ref]. “There was a considerable variability in digestibility of fiber components between individuals.”

Does fiber prevent the absorption of vitamins and other micronutrients as well? Maybe. I haven’t seen literature on the topic, but it makes sense that cellulose adsorbs a variety of molecules that are carried through the intestine undigested. Best to take your supplements separate from your fiber.

I am out on a limb recommending an ultra-high-fiber diet, and I suspect that results will vary widely among individuals. But what is not controversial is the health value of leafy green vegetables—the more the merrier.

Conclusions so far:

This much is clear: Green vegetables are good.  Animal protein is bad.

Beyond that, we might be tempted to interpret the Nutritional Geometry literature to say that “carbs are ok”.  I am wary of this conclusion, however.  It’s not just the standard warning that “mice are not people”. The benefits of a high-carb diet have only been shown in the context of severe protein restriction that I think is unrealistic for most of us. To be continued…

Next week: Metabolic Syndrome, Glycemic Load and The ketogenic Diet