I'm making final revisions to my book, "Darwinian agriculture
: where does nature's wisdom lie?" [they made me change the title, too] and my editor, at Princeton University Press, has asked me to cut two chapters. I agree that doing so will give the book a narrower focus, but I think some people might find them interesting. So here's the first of the missing chapters.
Beneficial toxins, evolutionary tradeoffs, and the health benefits of organic vegetables
"Early births are worth more than late in an increasing population, and vice versa in a decreasing one." -- Hamilton. 1966
What about food quality?
Early in 2011, a majority of the world's population could afford to buy enough food to meet their basic needs for protein and food energy, although this may not always be true in the future. But some diets are better than others. Vegetables appear to be particularly health-promoting.
Some of the income from my brother Tom's family's organic farm (near Corvallis, Oregon) comes from "community supported agriculture" subscriptions, where families pay an annual fee for a weekly food box from his farm. I once asked him whether people save money by buying these subscriptions.
"They save money on their medical bills," he explained. This is because one of his boxes contains more vegetables than most families would otherwise eat. Rather than waste vegetables they've already paid for, they eat them, presumably improving their health.
Why are vegetables so good for us? They provide fiber, vitamins, and antioxidants, all apparently beneficial, but can these explain all of their health benefits?
This chapter explores the hypothesis that low doses of natural pesticides, which plants make to protect themselves from harmful insects or fungi, may explain some of the health benefits we get from eating vegetables. Beneficial effects are hypothesized to result from tradeoffs between immediate reproduction and long-term health, with low doses of toxins shifting the balance towards long-term benefits. Although the various pieces of my argument are supported by experimental work with various animal species, combining these pieces and applying them to humans is quite speculative at this point. Readers bothered by speculation can skip this chapter without missing the other major conclusions of the book.
There is some evidence that vegetables grown "organically" (without artificial pesticides) may make more natural pesticides, although this isn't critical to my main point. For example, Alyson Mitchell and her colleagues at UC Davis measured flavonoids in tomato samples collected at LTRAS. Tomatoes grown organically had about twice the flavonoid levels of the same tomato variety grown using conventional methods.(Mitchell, et al. 2007) (Unlike many conventional-versus-organic comparisons, tomatoes at LTRAS were all the same variety, grown at the same time, by the same people.) Similarly, in another study, soup made from organic vegetables had more salicylic acid.(Baxter, et al. 2001)
Flavonoids have been reported to protect humans against cardiovascular disease and possibly cancer and dementia. Salicylic acid apparently reduces heart disease. Flavonoids and salicylic acid may promote human health, but that can't be why plants evolved to make them. So how do these chemicals benefit plants?
Flavonoids apparently benefit plants in various ways, including protection from ultraviolet (UV) light and protection from insects.(Harborne & Williams. 2000) Conventional and organic tomatoes at LTRAS are exposed to similar UV levels, however, so differences in flavonoid levels between organic and conventional tomatoes may be related to differences in insect populations. Similarly, salicylic acid plays a central role in plants' defense against fungi and other microbes that cause disease.(Loake & Grant. 2007) So maybe the reason that organic vegetables sometimes make more of these chemicals is that they are not sprayed to protect them from insects or fungal pathogens. Under this hypothesis, higher pest density on organic vegetables triggers more production of natural chemical defenses, such as salicylic acid or flavonoids.
There are many other differences between organic and conventional farming, of course. More research will be needed to determine whether higher levels of plant defensive toxins in organic vegetables are common or rare, and whether differences in pest control are really responsible. But I will leave those questions for others.
My focus here is on a second question: why might natural pesticides like flavonoids and salicylic acid be beneficial to humans? When I first started thinking about this question, I thought these two examples might just be coincidence. Humans are different from insects, so chemicals that poison them will not necessarily poison us. Just by chance, some of them might even turn out to be beneficial to humans. But I no longer have much confidence in this "coincidence" hypothesis.
The problem with the coincidence hypothesis is that the list of natural insecticides and fungicides that apparently benefit humans continues to grow. Examples include glucosinolates (found in cabbage and related plants), curcumin (found in turmeric), and resveratrol (found in grapes). Biologists Mark Mattson and Aiwu Cheng have argued persuasively that such benefits are too widespread to be coincidence.(Mattson & Cheng. 2006) Although others have suggested that these chemicals are beneficial because they are antioxidants, they point out that not all are antioxidants, and others are beneficial at doses where antioxidant benefits are unlikely.
Mattson and Cheng proposed an alternative hypothesis: although these are indeed toxins, harmful in large quantities (like aspirin), they are nonetheless beneficial in lower amounts.
There are, in fact, many reports of beneficial health effects from low doses of toxins, radiation, and other kinds of stress, such as high temperature. This strange phenomenon is known as hormesis.(Calabrese. 2004) What could explain these results? Mattson and Cheng argue that plant defensive toxins "stimulate cell stress-response signaling pathways which then protect neurons from damage." This may be true, but it can't be the end of the story.
If the protective processes that are turned on in response to toxins are always beneficial, then why aren't they turned on all the time? Always-on mutants must have arisen often over the course of human evolution. There must be many possible mutations in the signaling pathway(s) controlling these processes that would turn them on all the time, as argued in Chapter 4. So our ancestors with toxin-inducible mechanisms must have competed against ancestors in which the same mechanisms were always on. Why did inducible mechanisms win?
Tradeoffs between immediate reproduction and long-term health
If you guessed "tradeoffs", you win an organic tomato. Maybe the "beneficial mechanisms" induced by low doses of toxins are indeed beneficial in some ways, but harmful in others, just as the sickle-cell trait protects against malaria but reduces blood oxygen transport. We would need to measure costs and benefits in several different ways, under a range of conditions, before concluding that a response is uniformly beneficial.
Biologist Valery Forbes has made a good start. She reviewed published work on hormesis in various species.(Forbes. 2000) Various toxins had beneficial effects on some aspect of health, such as an individual's growth rate. But was there an overall benefit? She looked at overall growth rates of populations exposed to low doses of toxins. Of 98 studies, only one showed a statistically significant increase in overall population growth. (The "toxin" in that case was copper, which is actually essential in small quantities, as part of certain enzymes.) It appears that benefits of low-dose toxins can often be outweighed by tradeoffs.
One such tradeoff is that between reproduction, especially early reproduction, and longevity.
Tradeoffs between longevity and reproduction are key to a fundamental evolutionary question. It has been estimated that, if we eliminated aging, so we only died from accidents and diseases not related to age, then the average human lifespan would be 693 years!(Nesse & Williams. 1994) So why do we age?
Details differ, but the general answer to every "why" question in biology is the same: species are the way they are because they inherited alleles for traits that, in past environments, led to more descendants, relative to alternative alleles. In this case, natural selection hasn't eliminated aging because there are often tradeoffs between early reproduction and later reproduction, with only the latter depending on a longer life-span.
There are several direct risks associated with reproduction. Sexually transmitted diseases are a longstanding problem. Some of our male ancestors reproduced only after fighting for a mate. If you read the tombstones in an old cemetery, you will see that women often died in childbirth. Even when death in childbirth is excluded, repeated pregnancy tends to shorten lifespan, although there are complex interactions with factors like food supply. When food is scarce, the energy costs of pregnancy and lactation can reduce maternal health and survival. When food is plentiful, women with six or more pregnancies have a 70% higher risk of stroke, as well as higher risks of cardiovascular disease and obesity.(Jasienska. 2009)
There are also more subtle risks, linked to readiness to reproduce, rather than to reproduction itself. For example, high levels of testosterone tend to increase male reproductive success, but testosterone can also have negative effects on health, including risky behavior and greater susceptibility to infection.(Reed, et al. 2006, Schmid-Hempel. 2003) Blood pressure and insulin levels that are optimal for immediate reproduction are probably not exactly optimal for longevity.
Reproducing early, or the physiological changes that make early reproduction possible, has a long-term cost. Free-ranging female macaques show a strong genetic correlation between age of first reproduction and adult survival; reproducing earlier means dying earlier.(Blomquist. 2009)
Among the first to explain the evolution of aging as a function of such tradeoffs was the evolutionary biologist, George C. Williams.(Williams. 1957) Decades later, he worked with physician Randolph Nesse to write an influential scientific review article(Williams & Nesse. 1991) and a popular book(Nesse & Williams. 1994) on "Darwinian medicine." Both were among the inspirations for this book and are highly recommended.
Whatever the benefits to individual health and longevity, would alleles that delayed reproduction ever be favored by natural selection? Natural selection doesn't care how long we live, just how many children we have. Actually, this isn't quite true, and not just because natural selection doesn't have emotions. It turns out that the timing of reproduction can be very important, in ways that depend on conditions.
What conditions might favor delaying reproduction? Here's a clue: in species ranging from fruit-flies to monkeys, eating less lengthens lives. Rhesus monkeys allowed to eat as much as they wanted lived an average of 25 years, whereas those getting less of the same food (just enough to keep their weights at the lean end of normal) averaged 32 years.(Bodkin, et al. 2003) This is the same proportional increase as humans living to age 90 rather than 70. In another study using monkeys, dietary restriction appeared to be particularly valuable in reducing the frequency of diseases that normally increase with old age.(Colman, et al. 2009) The limited data on humans also appear to show health benefits from eating less, even for those who are not obese.(Heilbronn & Ravussin. 2003)
Why is dietary restriction beneficial? You might think that animals eating less would have less resources to invest in maintaining their bodies, so that food deprivation would shorten lifespan.
Will Ratcliff, Mike Travisano, Peter Hawthorne and I recently proposed an explanation for increasing lifespan with dietary restriction.(Ratcliff, et al. 2009) We think that food deprivation shifts our reproduction-versus-longevity switch towards longevity, sacrificing current reproduction for later reproduction. But why? An important clue, seen in both fruit-flies and nematode worms, is that food odors partly reverse the longevity increase from dietary restriction.(Libert, et al. 2007, Alcedo & Kenyon. 2004)
Food odors don't provide resources, but they do provide information. This information may be used by our bodies to tweak the timing of reproduction, thereby affecting lifespan as well. Could some effects of dietary restriction or low doses of plant toxins also be linked to information? If so, what is that information?
Dietary restriction or plant toxins may act as cues that, in past environments, predicted decreases in overall population size from starvation. Food odors, in contrast, usually predicted stable or increasing population size. This information is useful because, if population size is decreasing, delaying reproduction can actually increase fitness.
How can delaying reproduction increase fitness? When population size is decreasing, the genomes of offspring produced later will be a larger fraction of a smaller gene pool -- big frogs in a small pond. The gene pool is the sum of all the genomes in a population.
Remember that fitness is a relative measure. Evolution is a change in the relative frequency of different alleles, not the absolute number of individuals with those alleles. When population size is decreasing, alleles from individuals who reproduce later, including alleles for reproducing later, can dominate future generations.
Maximizing both early and late reproduction would be ideal, if that were possible. However, the tradeoffs discussed above mean that early reproduction often reduces later reproduction. Every time a stag fights for the chance to mate, he risks injury that could shorten his life. A plant that puts all available resources into seed production will have nothing left to help it survive the winter. (This is why I don't expect perennial grains will ever have high yield.) And, key to our hypothesis, human bodies revved up to reproduce early probably won't last as long, whether or not they actually reproduce early.
To summarize: when population size is decreasing, natural selection can favor delaying reproduction, if delaying reproduction increases the chance of surviving long enough to reproduce later. The potential relative-fitness benefit of delaying reproduction need not depend on whether conditions will be better next year; it only requires that overall population size decrease more than a delaying individual's likely reproduction (including the risk of dying before next year) decreases.(Ratcliff, et al. 2009)
William Hamilton, one of the most important evolutionary theorists since Darwin, noted the importance of overall population-size trends in his classic paper, "The moulding of senescence by natural selection"(Hamilton. 1966), quoted in the box that opened this chapter. Other evolutionary biologists have reiterated it since.(Pianka. 1999) However, many have assumed this point is "somewhat academic",(Charlesworth. 1980) because "a population with a negative growth rate would soon go extinct".(Hughes & Reynolds. 2005)
It is certainly true that no population can have negative population growth indefinitely. But most real-world populations fluctuate, like wild caribou, alternating between short-term increases and short-term declines. Although many human populations have increased over the last few decades, our ancestors went through repeated cycles of feast and famine. We showed mathematically that natural selection can favor delaying reproduction when reliable environmental cues predict that overall population size is about to decline. If population size declines enough, and delaying reproduction increases survival enough, then delaying reproduction can increase relative fitness even if fewer offspring will be produced later than could be produced now.(Ratcliff, et al. 2009, Denison. 2011)
What environmental cues predict population declines? Famine is one common cause of population declines. In ancestral populations, eating less was often a reliable indicator of a famine in progress. If an individual is unable to find enough food, maybe others are having difficulty as well. In that case, the population may be about to decline. So long as the hungry individual has enough fat reserves (or hoarded food) to survive until conditions improve, it may be better to delay reproduction, then add offspring to a smaller gene pool. This assumes that reproducing early in a famine would significantly reduce the chances of living long enough to reproduce after the population had declined.
Why do food odors reverse the longevity benefit of eating less?(Libert, et al. 2007, Alcedo & Kenyon. 2004) If an individual smells food, others are probably eating. Therefore, the overall size of the gene pool is less likely to decrease. So delaying reproduction may not be such a good idea.
Evolutionary tradeoffs, organic vegetables, and pesticides
What does all this have to do with organic vegetables? As discussed above, many vegetables contain low doses of natural toxins that plants make to defend themselves. This may turn out to be particularly true of vegetables that have not been protected by sprayed pesticides, although that is neither certain nor key to my main point.
I hypothesize that our ancestors consumed these chemicals mainly in "famine foods"(Salih, et al. 1991), eaten during population declines. This hypothesis is based on the assumption that many of our ancestors (human or prehuman) preferred to eat meat or sweet fruit, rather than bitter leaves. They only ate plant foods high in defensive chemicals when their preferred foods were scarce, that is, during a famine. If this is true, then consumption of plant defensive chemicals would have been a reliable predictor of near-term population decline. Natural selection therefore linked delayed reproduction (potentially increasing fitness over the course of past famines) to either starvation or diets high in plant defensive chemicals.
Do "famine foods" really improve longevity? If so, is this really a side-effect of partially suppressing reproduction? We have more-direct evidence from other species than from humans. Nematode worms eating their preferred food (live bacteria) reproduced earlier, but they didn't live as long as those on a less-preferred diet (Figure 6).(Houthoofd, et al. 2002) These results are fully consistent with the famine-food hypothesis, but there could be other explanations. Was the less-preferred diet so bad that it was impossible to reproduce early, even by risking earlier death? Or did it act as a cue that delaying reproduction was likely to increase fitness?
What about particular defensive compounds made by plants? Grape vines make more resveratrol in response to fungal infection.(Jeandet, et al. 1995) Were past famines often associated with fugal attacks on crops? Resveratrol extended nematode lifespan, but reduced early reproduction, consistent with tradeoffs and its possible role as a cue.(Gruber, et al. 2007)
Most research on the effects of eating plant defensive compounds have focused either on possible negative effects, e.g., of glucosinolates in livestock feed(Etienne & Dourmad. 1994) or on potential health benefits. The possible involvement of these chemicals in shifting tradeoffs between longevity and reproduction have received little or no attention.
Research publications on possible benefits of these chemicals sometimes mention reproduction, but they almost never include data on the timing of reproduction. For example, one study with fish reported that "resveratrol-treated females continued to lay eggs... when all the controls had died"(Valenzano, et al. 2006). But did later reproduction come at the expense of earlier reproduction? Those data were not included. Feeding fruit-flies curcumin, which kills some pathogenic fungi,(Kim, et al. 2003) made them live longer and "did not reduce fecundity";(Lee. 2010) but, again, data were not shown. Were there effects on timing of reproduction?
We need more data like those in Figure 5 -- or contradicting those in Figure 5 -- for a wider range of species and plant-defense chemicals, particularly at doses where they are likely to act as cues, rather than as antioxidants or acute toxins. (Mild toxicity may be a cue.) Some natural insecticides and fungicides may turn out to have only negative effects. Others may be beneficial for reasons unrelated to reproduction. But I predict that, at the right dose, many of these toxins will tend to delay reproduction, by triggering physiological or hormonal changes that also tend to increase long-term health.
Inherited responses to obsolete information?
In humans, these hypothesized responses to plant toxins would have been inherited from ancestors who survived and reproduced after famines. Apart from overall increases in food security, at least in rich countries, what has changed since then?
Plant breeders have greatly reduced toxin levels in most vegetables, relative to their wild ancestors. Wild potatoes contain such high levels of toxins that Indians often ate them with toxin-binding clay, and only when other food was scarce.(Johns. 1990) So shortages of potatoes were responsible for the "potato famine" in Ireland, but wild potatoes were famine food. Modern potatoes can still make high levels of toxins, but only when exposed to light. This is probably because potatoes exposed to light, at the soil surface, are more likely to get eaten by an animal than are potatoes safe underground.
Improvements in crop management may also have reduced toxin levels. Conventionally grown crop plants are often protected by sprayed insecticides and fungicides. Organic farmers may release beneficial insects that control pests. So the vegetables we eat today may contain much lower levels of natural pesticides than those eaten by our distant ancestors.
Still, vegetables usually have higher levels of toxins than either meat or fruit. There is a logical evolutionary explanation for this. If an animal takes a bite out of a plant and then stops, deterred by bitter toxins, the plant will probably survive. Take a bite out of mammal, however, and it is likely to die. So, there has been little or no selection to make mammals toxic to eat. (Insects that taste bad often live with groups of close relatives, so a predator that eats one is unlikely to eat its kin.) Fruits may make toxins to prevent animals from eating them too soon, like latex in unripe figs, but once the seeds are mature they benefit from animals eating the fruit and dispersing the seeds. Leafy vegetables and root crops don't benefit from being eaten, however, so they may still contain the same toxins (in lower doses) that our ancestors once ate in famine foods. Today, however, we are unlikely to get high enough doses of these natural toxins to hurt us. Instead, they may now act as beneficial environmental cues.
By eating these toxins, we are sending a message to our bodies: if you are eating this stuff, there must be a famine underway. If you have enough fat reserves to survive, don't reproduce now; wait until after the population crash. Set your hormone levels and blood pressure for survival mode. It's these physiological changes, which would have somewhat decreased short-term reproduction in our ancestors, that may explain some health benefits we get today from eating vegetables containing defensive toxins. Because we have more control over our own reproduction than most species, however, our actual reproduction may not always depend on differences in biological fertility.
If bitter or slightly toxic foods predicted past population declines, what about food odors? They may have provided the opposite cue, predicting population increases that favor immediate reproduction, whatever the long-term consequences for longevity. Are other sensory cues important? For example, could soft drinks be harmful partly because sweet tastes were associated with past food abundance and growing populations? If so, then maybe sweet taste itself could trigger physiological changes favoring reproduction over longevity. Two studies showing that sugar-free soft drinks can be just as harmful as those containing sugar are consistent with our hypothesis.(Dhingra, et al. 2007, Lutsey, et al. 2008) On the other hand, could kale's bitter flavor or the burning sensation caused by hot peppers be key to their health benefits?
If low doses of natural pesticides can improve health, at the expense of potential reproduction, what about synthetic pesticides? These chemicals can certainly be dangerous in high doses, but could they be beneficial in low doses?
This is a possible difference between our tradeoff hypothesis and the hormesis (beneficial stress) hypothesis of Mattson and Cheng. If I understand their hypothesis, it predicts that mild stress from a wide variety of toxins, perhaps including synthetic pesticides, should be beneficial. Under our hypothesis, our bodies might respond most to specific natural plant toxins, those to which our ancestors were exposed during past population crashes. Synthetic toxins might have similar benefits only if they somehow triggered the same responses.
But the key difference between our hypotheses is the role of tradeoffs. Tradeoffs are key to the "famine food" hypothesis, whereas their hormesis hypothesis does not appear to depend on tradeoffs at all.(Mattson & Cheng. 2006) This is what made me question their hypothesis in the first place. Without tradeoffs, why not turn antistress mechanisms on all the time?
A broader view of the famine-food hypothesis
To recap our hypothesis: health benefits from eating less, or from eating vegetables containing plant defensive toxins, are due to biological responses, inherited from ancestors who increased their relative fitness by delaying reproduction when environmental cues predicted population decline. Changes in hormone levels or blood pressure that would have delayed reproduction in our ancestors may increase lifespan today.
If our hypothesis is correct, it could lead to medical treatments or changes in life-style that would increase potential longevity, at the expense of potential reproduction. Would this be a good thing? For example, would we be willing to sacrifice teen pregnancy, to have longer and healthier lives?
One concern would be effects of increased lifespan on population growth. But, if birth rates and deaths from old age were each cut in half, population growth would actually slow significantly, at least in the short run. This is because there are many more people of reproductive age than there are really old people, especially in those countries with the fastest population growth. So halving the birth rate would have much more effect than halving the death rate would.
On the other hand, a decrease in potential reproduction would not necessarily translate into a proportional decrease in actual birth rate. Moderate changes in hormone levels, for example, might extend lifespan without greatly affecting family size. Couples who really want more children could probably figure out how to make this happen, even with slightly lower fertility. (Research to test the famine-food hypothesis in humans should therefore look for correlations between diet and variables linked to potential reproduction -- age of menarche, testosterone levels, etc. -- rather than actual reproduction.) Similarly, an increase in potential longevity might have little effect on actual longevity. In countries where malaria, AIDS, malnutrition, violence, or accidents are major causes of death, a decrease in age-related illness would have less effect on overall population growth.
There may be additional complicating factors. For example, if people expected a longer and healthier old age, would they have more or fewer children, and when? Increasing the elderly population, even from a small base, could have a major impact. This would be particularly true in societies where the elderly either use more resources (because of entitlements or accumulated wealth) or make more positive contributions (because of accumulated experience) than the population as a whole. If we have more old people, but old people are healthier than today, that could have major implications for hospitals, pension funds, real estate, and universities. It may be possible to predict these effects, but I won't attempt to do so here.
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