Intermittent Thoughts on Intermittent Fasting - The Fast #2: Health & Longevity Effects of Intermittent Fasting

Image 1: Any roundworms reading this? I hope you know that by not eating enough and feeling miserable you can extend your lifespan ;-)
Thanks Caenorhabditis elegans, or "C. elegans", almost everybody who is able to read a newspaper or online magazine will have heard of the miraculous effects of calorie restriction and fasting on longevity (of this worm!). Since I assume that you possess more gray matter than this transparent nematote, you will probably have asked yourself how, or rather if these results from a worm with an average lifespan of 2-3 weeks translate to human beings,... well, all I can tell you is that leading a miserable life of lifelong dieting appears to work in non-human primates, as well (Kemnitz. 2011). Now, the obvious question is:
How does all that relate to Intermitent Thoughts on Intermittent Fasting? Obviously, none of the roundworms or rhesus monkey's followed Martin Berkhan's intermittent fasting approach, did they?
No, I have not seen pictures of abes on, either, so I suppose they did not follow Berkhan's approach, but - and this is the likewise fascinating, as well as surprising, connection - there is scientific evidence that intermittent fasting could reproduce some of the beneficial effects of caloric reduction while avoiding a whole host of its undesirable side-effects. Reason enough for me, to devote this episode of the increasingly popular Intermittent Thoughts on Intermittent Fasting series to the non-cosmetic health effects of intermittent fasting (I know that's not as getting ripped and jacked, guys ;-)
Figure 1: Ramadan fasting leads to profound beneficial changes in inflammatory markers (left) and blood lipids (right) in 20 healthy male non-obese volunteers aged 23-39 (data calculated based on Aksungar. 2006)
We touched on one of this unsexy, yet vitally important health-benefits at the end of the last installment on the metabolic and endocrine effects of fasting, already: the beneficial effect on insulin resistance (as measured by a +44% increase in the inverse of the long-term marker of insulin resistance 1/HOMA-IR and the slight increase in QUICKI) Shariatpanahi et al. had observed in 55 ramadan fasting subjects (Shariatpanahi. 2008) for example constitutes one of these "boring side-effects", of which many dieters fail to realize that improvements in insulin sensitivity or reductions in inflammatory markers and C-reactive protein (cf. figure 1, left), as they were reported by Aksungar et al. in a 2006 study on the effects of religious "intermittent" fasting (Aksungar. 2006) facilitate weight - and more specifically - fat loss.
Image 2: Would the issue of dehydration distort the results of Ramadan studies and thus render them irrelevant for our argumentation? (photo Offline Clinic)
As in almost every episode I want to make a few brief statements regarding the "Ramadan model of intermittent fasting". I have already discussed its advantages over "over-other day" or "alternative day" fasting in the second installment of this series and I have hinted at possible problems related to the restriction of water intake within the fasting period in the third installment of the series. Now, in view of the general recommendation to drink more and more frequently to avoid dehydration (USDA), it seems prudent to verify that potential beneficial health effects of fasting are not masked by detrimental side effects of dehydration, if we - once again - want to rely on the available data on religious fasting as part of our argumentation. In a paper published in the European Journal of Clinical Nutrition in 2003, Leiper, Molla and Molla report that despite the fact that "[d]uring the daylight hours of Ramadan fasting, practising Muslims are undoubtedly dehydrating", it is neither "clear whether they are chronically hypohydrated" nor have there been any "detrimental effects on health [...] directly attribut[able] to negative water balance at the levels that may be produced during Ramadan" observed in any scientifically relevant studies (Leiper. 2003). It is thus relatively safe for us to assume that we can neglect he influence of potential dehydration in our initial analysis of respective studies.

Now, what about the longevity effects?

Image 3: The effects the calorie restriction had on the ape on the right is certainly impressive, when you compare it to his 27.6 year old age-mate on the left - would be interesting to see how an "intermittently fasted version would end up ;-) (img. from the Irish Medical Times)
With or without the beneficial effects on cardiovascular risk markers, the question still remains: "Can intermittent fasting mimic the longevity effect of calorie restriction without the constant cravings, continuous hunger and all sorts of "human" problems that won't show in studies on yeast, worms, rodents or even apes (see image 3)?"

In order to answer this question, we will first have to give a clear cut definition of what our understanding of intermittent fasting is, in this context, because, obviously, if we coupled our (intermittent) fast with a a deliberate and severe calorie restriction we would probably end up like Canto, the ape from the the longevity study in image 3 - old, but miserable. What we want, on the other hand, is an intermittent fast, where - within the feeding window - we are allowed to eat to satiety... similar to what we are seeing in religious fasting: no calorie counting and perceived (when compared to normal meal sizes) overeating.

Now, we do already know from the studies cited above (and in previous installments of this series) that one month on a dietary regimen like that provides considerable benefits as far as weight loss, insulin sensitivity, blood lipid ratios (! this is important, because we are knowledgeable enough to give a f*** about total cholesterol & co) and inflammatory markers, all of which are associated not only with an increased life-expectancy (Danaei. 2010), but, more importantly, with an increased life-quality and neurological health (Bronwen. 2006) up into the old(er) ages. From the same studies, we do yet also know that breaking the fast, and returning to our old dietary habits returns these markers to baseline (cf. post values in figure 1). What we do not know, however, is whether ...
  1. intermediate improvements in correlates of health and longevity as they can be observed during intermittent periods of Ramadan (intermittent) fasting provide any, or even significant longterm health benefits, and
  2. longterm (as in for years and decades) intermittent fasting would not over months or years lose its effect, or even worse, be detrimental to our overall health and thus reduce not extend our life-expectancy and/or life-quality
From rodent studies we already know that a life-long alternate-day feeding protocol increases lifespan in the absence of any caloric reduction (Goodrick. 1990; Mattson. 2000). Evidence that similar beneficial effects, at least as far as mortality from chronic disease is concerned, would occur in human beings comes from a 2007 study by Varaday and Hellerstein (Varaday. 2007), who do yet remark that (as I already pointed out) "more research is required to establish definitively the consequences of ADF [alternate day fasting]".

The circadian clock hypothesis

A finding from alternative day fasting studies that may be of paramount importance in view of the "quality of life"-aspect, is the increase in brain-derived neurotropic factor (BDNF) that has been observed in animal studies. BDNF is involved in brain development and plasticity and its (intermittent) fasting-induced elevation could explain the neuroprotective effect of respective feeding patterns (Duran. 2001). In a review of the literature, Fory and Miskin do yet remark that (Froy. 2010)
[...] BDNF could not be [directly] linked to the neuro-protective effects in the brain of calorically restricted rats, but increased levels of another neurotrophic factor, glial cell line-derived factor (GDNF), were correlated with neuro-protection of a calorically restricted primate model of Parkinson's disease. Interestingly, BDNF is also a component of the hypothalamic melanocortin pathway that controls food intake and body weight in adult mice, and it has been implicated in the regulation of energy metabolism.
After all, the scientists believe that IF exhibits part or even all of its effects by (re-)setting clock genes, a hypothesis which despite having its merits would yet lead us into theoretic considerations with little merit to our "intermittent thoughts" on the real-world outcomes of intermittent fasting, which is why I will, at this point, skip forward to the results of a 1999 study into the relation of adipose tissue size and reductions thereof to longevity.

Is it not about eating less, but just about getting leaner?

Image 4: When we are talking about the benefits of losing body fat, this obviously does not imply you have to get in Phil Heath Mr. Olympia '11 shape to live longer (photo
In the introductory paragraphs of this installment of the Intermittent Thoughts on Intermittent Fasting series I somewhat ridiculed the idea of changing one's whole life to get "ripped and buffed", now, after revisiting some of the studies and observing the close correlation of improvements in metabolic health markers, reductions in body fat and consequent life-extending effects of (intermittent) fasting, the central question of Nir Barzilai's and Gaurav Gupta's 1999 paper Revisiting the Role Fat Mass in the Life Extension Induced by Calorie Restriction seems by no means far fetched: What if ain't inflammation and insulin resistance & co that make us fat and reduce our lives, but being fat that leaves us insulin resistant, inflammed & co and thusly reduces our life-expectancy? The answer, according to Barziilai and Gaurav, is simple (Barzilai. 1999):
In fact, all of the benefits of CR on the neuroendocrine system and those related to the improvement in glucose homeostasis can be attributed to decrease in adipose cells and their products.
Probably too simple and above all difficult to treat with a drug and thus not profitable enough to be accepted by the medical establishment. Now, if this would be the case, intermittent fasting would in fact provide the sought-after silver bullet to leading a leaner, healthier life, as both the anecdotal reports on the Net, as well as the the majority of the studies that have been cited in this, as well as the previous installments show quite conclusively that going without food for periods <24h is capable of reducing body fat stores, while preserving lean muscle (and bone) mass. But why, or better how does that work?

Intermittent fasting, fat reduction, health improvements and the cyclicality of life

Illustration 1: It probably is the magic interplay of AMPK and mTOR that produces such remarkable transformations as Duong Nguyen's. We will delve deeper into the their reciprocal interaction in the next installment of the Intermittent Thoughts on Intermittent Fasting Series
Due to its cyclic nature intermittent fasting seems to temporarily produce similar "reductions in protein synthesis" (Barrows. 1978) as the ones which have been established as the fundamental mechanisms of the life-extending effects of calorie restriction as early as in the late 1970s and of which we know today that they partly mediated by an AMPK-induced downregulation of the mTOR pathway. In that, this transient AMPK response to intermittent fasting, which most intermittent fasters further stimulate by exercising in a (semi-)fasted state, appears to be profound enough to stimulate or, according to some recent research (cf. Canto. 2010), we should probably say "sustain" the SIRT1-pathway to an extent that allows dieters to benefit from its immediate fat-mobilizing effect on white adipocytes (Picard. 2004) and its ability to maintain telomer length (and subsequent longevity, cf. Palacios. 2010) without the unwanted muscle-wasting side-effects of prolonged fasting periods.

The fasting induced AMPK expression is yet only one part of the cycle, of which we have learned in this installment that it is responsible for both, the "cosmetic" effects on body fat, which could, after all, be causative and not just corollary or even subsequent to improvements in insulin sensitivity (cf. What Comes First: Inflammation or Obesity?), lipid profiles, and the whole string of beneficial health effects which irrefutably contribute to the longevity effect of inhumane low-calorie diets. In view of the fact that another valuable Sunday afternoon is drawing to a close, the discussion of the second player in this cycle, the mammalian Target of Rapamycin, or in short mTOR, will yet have to be postponed to the next episode of the Intermittent Thoughts on Intermittent Fasting Series - so stay tuned, keep the questions and comments coming and don't forget to check back on Thursday to see what AMPK and mTOR are doing to our man at the 2012 wheelchair nationals, Adelfo Cerame!
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