Our Longevity Diet

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.

In the past I’ve heard several claims that intermittent fasting can help prevent cancer, but in following the scientific literature, I’ve seen little evidence behind this claim. Now, someone from a discussion group brought this study to my attention:

Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice

Basically, the study not only shows that both calorie restriction and fasting can help make significant delays in the onset of cancer in mice bread to develop that disease (that’s what the p53 deficient part means), but they also show that the effect is present even when the calorie restriction or intermittent fasting is started later in life, rather than at adolescence. Too many of the existing studies of CR and IF look at the effects on animals that begin in adolescence and continue throughout their lives. I’d like to see more studies examine the effect of starting these dietary protocols later in life, and also the effect of starting early in life but then abandoning the protocol to return to ‘normal’ (i.e. continuous) eating.

And while the study shows cancer was ‘delayed’ rather than prevented, the difference is only semantic. Delay cancer long enough that you die of something else, and it has effectively been prevented. The mice were genetically prone to develop cancer — unless you have Li-Fraumeni Syndrome you are probably not so prone.

This study did show that calorie restriction was more effective than intermittent fasting, but the intermittent fasting regime used involved fasting just one day per week — it would be more interesting to see the results if ADF (alternate day fasting) were used. The bottom line seems to be that it is never too late to start benefiting from intermittent fasting. The beneficial effects are probably much stronger for those who start in early adulthood, but even us old fogies can reap some benefits.

A study reported last month noted that researchers have known for a while that Type II Diabetes is associated with high levels of visceral (or Belly) fat, while subcutaneous fat (below-skin, especially in hips and buttocks) is not. The study found, surprisingly, that it was not the presence of belly-fat so much as the absence of subcutaneous fat that leads to diabetes. That is to say, visceral or belly fat does not have a negative effect, but rather subcutaneous fat has a positive effect on insulin sensitivity, which in turn correlates with the development of Type II Diabetes.

People who have high levels of both types of fat are at much lower risk for diabetes than those who have only belly fat. And those with only subcutaneous fat are even less likely to develop diabetes. The researchers suggested that subcutaneous fat may produce certain hormones, called adipokines, that produce beneficial metabolic effects.

Now another study was released that says pretty much the opposite:

Our study found lipid release from abdominal fat was substantially elevated during the night, which may be a primary mechanism leading to insulin resistance, a strong risk factor for type 2 diabetes.

This study seems on shakier ground, so far as the basic logic goes. They observe that belly fat releases lipids, and jump to the conclusion that this is related to insulin resistance — without any proposed (let alone observed) mechanism for it to do so. It is an observed correlation, with no known causality relationship.

This is a good example of why following the scientific studies can be so confusing. You need to look critically at these reports, and judge the probability of their being accurate. But often we lack the detailed information on study design and implementation that would allow us to accurately judge the results.

In any case, we may assume that if lipids from belly fat were related to insulin resistance, then intermittent fasting may exert a positive effect by limiting the release of lipids during fasting periods. Of course, that is just speculation — but it is consistent with the observed beneficial effect of intermittent fasting on insulin sensitivity.

A report today describes the autopsy results for the examination of the brain of a woman who died at the age of 115 years. There were absolutely no signs of atherosclerosis (narrowing of the arteries) or beta-amyloid deposits (a characteristic of Alzheimer’s disease).

The woman had undergone neurological and psychological examinations at the age of 112 and 113, and showed no signs of dementia or problems with memory or attention at that age. She was alert and involved, interested in national and international politics. She lived in a residential care home from the age of 105 due to poor vision, but her brain and intelligence compared favorably with people forty years younger.

I have not found any detailed biographical reports on this lady, so we don’t know her economic status or life history, but from her age we know she lived through the trying times of World Wars I and II, as well as the Great Depression. It is not too far-fetched to imagine that she experienced some caloric restriction and/or involuntary fasting during those years.

I have yet to see any studies on intermittent fasting that allow the subjects to go back to unrestricted diets after a period of time, and still continue to follow-up on health and longevity measures. My impression from the study reports we do have, however, make me think that calorie restriction or intermittent fasting during early adulthood may be more beneficial, in the long run, than the same diet initiated later in life. By the time we reach middle-age, much of the damage is done already.

Whatever the cause of this woman’s longevity — lucky genes or just a freak of nature — she is proof that degeneration of the brain is not an inevitable consequence of aging. Other studies show that challenging the aging brain to learn new things is one way to help stave off deterioration. We are hoping intermittent fasting will also help.