Our Longevity Diet

A new report on caloric restriction (CR) came out today. You will remember that CR is a method that has been known to extend lifespan in animals for more than 70 years now, while our intermittent fasting (IF) technique has only been studied for the past 20 years or less. Most studies have shown that IF has all the benefits of CR, without the need to restrict calories, so people often assume CR studies are always relevant to IF — but there are recorded differences between the two methods.

First, let’s look at the the new report, called Differences Between People And Animals On Calorie Restriction. This study seems to rely primarily on the measurement of Insulin-Like Growth Factor 1 (IGF-1), which is itself rather surprising since IGF-1 seems to be one of those hormones that are beneficial at certain levels, while more or less are detrimental — yet the exact optimal levels don’t seem to be known yet. Animal studies of IGF-1 in CR animals generally shows a reduction, but when researchers conducting this study looked at real people who voluntarily have undertaken CR diets, their IGF-1 levels were indistinguishable from people on normal American diets. When some of these CR dieters were asked to reduce their protein intake, their IGF-1 levels fell substantially, mimicking the results found in CR animal studies. The above report states that:

In the majority of the animal models of longevity, extended lifespan involves pathways related to a growth factor called IGF-1 (insulin-like growth factor-1), which is produced primarily in the liver. Production is stimulated by growth hormone and can be reduced by fasting or by insensitivity to growth hormone.

The problem is, there is no hard evidence that IGF-1 levels are a major factor in the longevity effect of CR. Certainly, the evidence suggests that the insulin pathways are relevant, but this particular link in the chain has not been shown to be of major significance. In fact, an earlier study: Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake — showed that IGF-1 was increased in IF animal experiments, while it was reduced in CR animals. Yet both groups of animals showed the increased longevity that sparked interest in the protocols to begin with.

Another recent study: Hormone May Hold Key To Helping Elderly Men Live Longer showed that, at least for one group (elderly men) increased IGF-1 levels were associated with greater longevity, largely expressed through reduced cardiovascular risk. In that study, where researchers evaluated 376 healthy elderly men between the ages of 73 and 94 years:

Subjects with the lowest IGF-1 function had a significantly higher mortality rate than subjects with the highest IGF-1 bioactivity. These results were especially significant in individuals who have a high risk to die from cardiovascular complications.

The picture is not a simple one, however, because high IGF-1 levels have also been associated with higher risk of cancer. It seems, in short, that IGF-1 can help cells live longer — even if those cells are cancerous. Researchers thought that the lower IGF-1 levels in CR animals was indicative of a lowered cancer risk, but the IF studies suggest something else is at work here.

When animals are given CR diets, they receive their normal diet at reduced levels. With humans trying to emulate these CR benefits, their concern for nutrition leads them to increase the percentage of protein in their diets, and the results in regard to IGF-1 are different than those in the animal studies — but IF dietary results suggest that may not be such a bad thing. More IGF-1, in the absence of cancer, is probably a good thing — within limits.

Scientists have argued for some time now on exactly what mechanism drives aging and death. Two different predominant theories have been competing for the past thirty years: Bust vs. Rust.

The bust-down theory claims that genes are responsible for senescence, and after a roughly fixed time span they trigger cells to break down and cease repairing themselves. Evidence in support of this genetically driven model are the observations that certain species are long-lived, while others die young. Also, among humans, longevity has been seen to run in families. The problem with this theory is that it implies the typical age-span for a species is the result of biological evolution, yet much aging (at least among species such as humans) occurs after reproduction stops. Explaining a mechanism by which a feature can evolve when it does not affect reproductive success has been difficult.

The rust theory, on the other hand, suggests we just wear out. Disease, toxins, and especially free-radical oxidation damage, gradually accumulates until the body is no longer able to repair itself. Evidence in support of this theory includes the observation that calorie restriction (CR) and intermittent fasting (IF) can greatly extend the lifespan of study animals. The best available evidence suggests that these practices may improve the repair mechanisms in the body, hence holding off aging for a while.

But while CR and IF have been shown to extend life by as much as 50% or more, the animals in these studies still die. Clearly, these methods slow the aging process, but do not stop it. Thus many researchers came to believe that a combination of the two theories was probably more-nearly correct. Aging is affected by the environmental factors of the ‘rust’ theory, but the ultimate limits are genetically programmed.

Earlier research has shown that it is possible to greatly extend the lifespan of fruit-flies through  a kind of selective breeding program that controls what age the flies are allowed to reproduce at. Now another study has identified the exact genetic mechanism for aging in flatworms. According to that report:

Comparing young worms to old worms, Kim’s team discovered age-related shifts in levels of three transcription factors, the molecular switches that turn genes on and off. These shifts trigger genetic pathways that transform young worms into geezers.

As part of the research, they exposed some of the worms to environmental stresses such as heat, free-radicals, radiation and disease, and then measured the activity of the elt-3 transcription factor, which they found to be the controlling chemical in aging. None of the stress factors induced changes in elt-3 levels. The researchers conclude that genetically controlled changes in elt-3 are largely responsible for aging in the worms.

If confirmed in other animals, this shifts the balance back in favor of a strongly genetic source for aging, but it also provides a chemical target and pathway for interfering with the aging process. As with most research in this field, it is still way too early to tell — but we see progress is being made.

So far as our personal Intermittent Fasting regime is concerned — we never really expected it would help us live much longer than normal, since we started too late in life to reap the full benefits. At best we can hope for an extra 10% (i.e. living to 88 rather than 80). Our main motivation is the evidence that for those remaining years we are likely to be much healthier under the IF lifestyle than otherwise.

Food affects the brain. Well, duh … why don’t I find that headline surprising. Actually, the full headline (not being so succinct as I am) reads: Scientists Learn How Food Affects The Brain: Omega 3 Especially Important. The study being reported is simply an analysis of the literature, so it summarizes all the preceding studies on the subject — I guess that’s why the results are so unsurprising.

The main points of the report are that we need omega 3 fatty acids, probably more than we typically get in a normal diet. Salmon seems to be the best source for these, though tuna has them to a lesser extent, and even walnuts and kiwi fruit are sources of some omega 3 — but the report notes that particular types of omega 3 are more beneficial than others, such as docosahexaenoic acid, which is abundant in Salmon.

The report also cites the benefits to the brain of folic acid — a supplement that used to be recommended primarily for women who were, or might become, pregnant. Not only is folic acid essential for the proper development of a fetus, it is an important nutriment for efficient brain functioning.

This report also mentions something called brain-derived neurotrophic factor (BDNF) but that seems to be produced in the brain, rather than derived from food. The news report seems to associate BDNF with curcumin, without explicitly stating that a relationship exists. Never the less, curry (which contains high levels of curcumin, or the spice cumin) is also beneficial to brain functioning — whether by stimulating or facilitating BDNF is left to us to conjecture.

Bringing the discussion around to intermittent fasting, the report also states that:

A long-term study that included more than 100 years of birth, death, health and genealogical records for 300 Swedish families in an isolated village showed that an individual’s risk for diabetes and early death increased if his or her paternal grandparents grew up in times of food abundance rather than food shortage.

so that:

Controlled meal-skipping or intermittent caloric restriction might provide health benefits, he said.

Well that is cautious enough, isn’t it? Evidence certainly suggests that intermittent fasting WILL improve brain functioning, along with most of the body’s other systems — with or without caloric restriction. Somehow it is not greatly surprising that it is possible to pass some of that benefit on to your children, but why would it benefit grand-children? And particularly through the paternal line? I’ll have to try to track down the original study mentioned, to see if it can offer any plausible explanation.

The life-extension effect induced through caloric restriction (CR) or intermittent fasting (IF) has been studied more extensively in animal models than amongst human subjects — people just live too darn long for quick study results. A couple years ago researchers suggested that sirtuins might be responsible for the longevity effect observed in CR and IF.

Then came a study that showed fruit flies lived longer on a calorie restricted regime when Sir2 was absent — the opposite of the expected effect. Sir2 is a sirtuin in fruit flies that corresponds to SirT1 in mammals. Now further research indicates that brain cells from rats react better to oxidative stress when SirT1 is not present, suggesting that elderly brains may be harmed by the presence of SirT1.

Sirutuins like Sir2 and SirT1 play a complex role in metabolism, and their activity can not be clearly categorized as either beneficial nor harmful to longevity. More likely, they have some effect on processes that directly affect lifespan, such as glucose metabolism, antioxidant activity and insulin sensitivity.

Biologists are looking for the ’smoking gun’ (or guns) responsible for aging. It’s probably not the sirtuins, though they do play some role in the process. It can seem disheartening to see a promising line of research lead to a seeming dead-end, but in science negative results can sometimes be as helpful as positive findings, in that it further narrows the field and helps better focus attention on relevant factors.

One of the concerns about most calorie-restriction and  intermittent  fasting studies, is that they use animals, and they put them on the study diet when they first reach maturity, and continue until the animal dies or the study ends. That doesn’t translate into real-life human experience very well. A big question, for example, is whether or not intermittent fasting is beneficial if it is started later in life, rather than at early maturity.

A 2005 study titled Mitochondrial production of reactive oxygen species and incidence of age-associated lymphoma in OF1 mice: Effect of alternate-day fasting looks at older (i.e. ‘middle-aged’) mice to see if the know beneficial effects of fasting can be instigated later in life. Here is a quote from the abstract:

Alternate [day] fasting, that was initiated in middle age mice through a 4 month period, reduced significantly the incidence of lymphoma (0% versus 33% for controls). No remarkable difference was observed in the overall food consumption between alternate-fed (AF) and ad libitum (AL) mice, suggesting that the efficacy of alternate fasting did not really depend on calorie restriction.

This is good news, since many of the other beneficial effects of intermittent fasting observed in rodents have been confirmed in humans. The above study went on to observe that there was less oxidative stress observed in mitochondria of the fasting mice, compared to the control animals. This is the type of basic biological function that transgresses species, and may well function similarly in humans as in mice.

The focus of research in the past couple years seems to have shifted away from anti-oxidant behavior to particular  metabolic regulators and messenger chemical systems, but anti-oxidants have already demonstrated substantial beneficial effects on health and longevity. High anti-oxidant foods have the benefit of also tasting good, so it is no sacrifice to consume lots of them. When I lived in Michigan, my favorite was blueberries, but now that I’m in Mexico, those are hard to come by. Instead, I eat lots of chocolate — not sweetened, fattening, chocolate bars, but natural chocolate combined with spices and used as a sauce (check out Chicken Molé at your local Mexican Restaurant, for example). I also drink red wine for the ultimate anti-oxidant, resveratrol. Pomegranates, tomatoes, broccoli, garlic, spinach, tea and coffee, strawberries, and avocado are all high in anti-oxidants, and probably more beneficial than ever when combined with an intermittent fasting diet.

Continuing our theme on intermittent fasting studies done on human subjects, today we look at a study called Alternate-day fasting in nonobese subjects: effects on body weight, body composition, and energy metabolism, published in January 2005. In this study, eight men and eight women practiced alternate day fasting — quite literally — they ate one day, then fasted from midnight that day to the following midnight. The study lasted three weeks.

Before describing the results, let me jump to the author’s conclusion:

Conclusions: Alternate-day fasting was feasible in nonobese subjects, and fat oxidation increased. However, hunger on fasting days did not decrease, perhaps indicating the unlikelihood of continuing this diet for extended periods of time. Adding one small meal on a fasting day may make this approach to dietary restriction more acceptable.

This is almost exactly the type of diet Isabel and I follow, excepting the timing of the fast. I can just visualize those subjects waiting for midnight, then eating a big meal just before sleeping. Knowing they would fast again the following day, they probably ate a lot again just before going to sleep at the end of their eating day. So they slept with a full stomach — but were awake (and hungry) during all the difficult hours of the fast. As I’ve stated before, making this regime comfortable requires careful selection of the timing for your fast!

So, what were the results? Well, the subjects lost, on average 2.5% of their initial body weight, even though they were not restricted in how much they could eat on their eating days. In fact they were told they would need to eat ‘twice as much’ as normal to maintain their weight. Hunger, not surprisingly, did not decrease over time. I don’t know why anyone would expect that it might. Hunger doesn’t increase either — one is either hungry or not — with persistent intermittent fasting you get used to being hungry at times, but knowing food is coming soon makes it more bearable.

Measures of resting metabolic rate, respiratory quotient, glucose and ghrelin levels were unchanged, excepting that respiratory quotient decreased on the last day, which involved fasting longer than the usual 24 hours (the researchers obviously did not want the inconvenience of needing to test the subjects at midnight to get fasted results, so they had to fast until 7:00 AM the next morning as well). The only big change, besides the weight loss, was in insulin, which was down an average of 57% after the 31 hour terminal fast.

Obviously, this study was highly flawed in design. There was no measurement of what or how much the subjects ate on their eating days. Subjects even reported eating more than usual on their last eating day because they knew they needed to fast longer than usual afterwards! That alone undoubtedly affected all of the measurements taken.

One of the few Intermittent Fasting studies to use human subjects was Effect of intermittent fasting and refeeding on insulin action in healthy men by Nils Halberg, Morten Henriksen, Nathalie Söderhamn, Bente Stallknecht, Thorkil Ploug, Peter Schjerling, and Flemming Dela, published in July 2005. In this study a very small population of eight healthy men undertook an alternate day 20 hour fast for two weeks (kind of like Fast-5, but only every other day). They fasted from 10:00 PM one night to 6:00 PM the following night, every second day, so there was a total of seven 20 hour fasts over the 15 day period. They were instructed to eat more than normal on the non-fasting days, to maintain their weight, but not to change the types of foods they ate.

There was no significant weight-loss (as one might expect given the compensatory over-eating on non-fasting periods). Yet they did find significant improvement in glucose metabolism, especially insulin sensitivity.  They did not find evidence for the muscle-loss that had been observed in long-term fasts of 72 hours. According to the researchers:

This experiment is the first in humans to show that intermittent fasting increases insulin-mediated glucose uptake rates, and the findings are compatible with the thrifty gene concept.

By ‘thrifty gene’ they mean that our bodies are likely adapted to Late-Paleolithic eating habits. Indeed, in their introduction, the authors state:

Insulin resistance is currently a major health problem. This may be because of a marked decrease in daily physical activity during recent decades combined with constant food abundance. This lifestyle collides with our genome, which was most likely selected in the late Paleolithic era (50,000–10,000 BC) by criteria that favored survival in an environment characterized by fluctuations between periods of feast and famine. The theory of thrifty genes states that these fluctuations are required for optimal metabolic function.

Our take on this is that even very limited fasting, such as imposed by their study, can be beneficial for health. Our fasting schedule is really not much different, except it is slightly longer, 23 hours instead of 20, and our schedule is more balanced — which we find easier and much more comfortable — and we maintain it fairly constantly, not just for a couple weeks.

I find no reason to suspect our genetic adaptation to food intake during the Late-Paleolithic was substantially different from earlier times, when hunting-gathering also prevailed, so it might be more accurate to suggest we are still largely adapted to pre-agricultural food habits. No doubt we have undergone substantial adaptation during the past 10,000 years, but probably not enough to overcome the preceding 200,000 or more years.