Calorie restriction delays disease onset and mortality in monkeys

New study (Colman et al, 2009) in this week's issue of Science on the effect of calorie restriction over a 20 year period in rhesus macaques. Researchers at the Wisconsin National Primate Research Center examined monkeys under 30% CR and controls matched for baseline intake, age, and weight. According to the abstract:

Caloric restriction (CR), without malnutrition, delays aging and extends life span in diverse species; however, its effect on resistance to illness and mortality in primates has not been clearly established. We report findings of a 20-year longitudinal adult-onset CR study in rhesus monkeys aimed at filling this critical gap in aging research. In a population of rhesus macaques maintained at the Wisconsin National Primate Research Center, moderate CR lowered the incidence of aging-related deaths. At the time point reported, 50% of control fed animals survived as compared with 80% of the CR animals. Furthermore, CR delayed the onset of age-associated pathologies. Specifically, CR reduced the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy. These data demonstrate that CR slows aging in a primate species.

Their general findings indicate a clear quantifiable effect of CR in reducing both mortality and age-related morbidities (cancer, cardiovascular disease, metabolic derangements) as well as age-associated loss of gray matter:

Food for thought, though confounding issues such as frequency of eating rather than total amount of caloric intake are not directly addressed.

Antioxidant supplements curb exercise benefits?

Blurb in the NYtimes today covering some recent research suggesting that antioxidant supplementation may prevent some of the exercise-induced benefits of exercise (specifically, improvements in insulin sensitivity).

I haven't had a chance to read the research paper yet, but it is available via OpenAccess here.

Adaptation

I was reading some literature on the compressive loads experienced by the spine during deadlifts when I came across some interesting data from a study by Granhed et al. (1987). They calculated loads on the L3 vertebrae of experienced powerlifters (all of the lifters in the study were pulling over 200 kg, with a few over 300 kg). What I found interesting was that the authors reported the the annual lifting tonnage from the lifters' training records. I've re-plotted the data below:
This is essentially Granhed et als third figure, although I've switched the axes to reflect my belief in the causal variable, and included the weights for the lifters and data for control subjects.

The data isn't exactly surprising, and there's good evidence that resistance-exercise makes bone stronger (Suominen, 1993). Of course, the study was cross-sectional, so it's unclear how much increase in bone mineral content these lifters saw over the course of their individual training. It's entirely possible that only lifters with strong spines ever manage to lift a lot of weight over the course of a year, and that they experienced little or no adaptation in bone density from lifting heavy weights. Undoubtedly, this bias exists to some degree; the deadlift is an incredible selective pressure after all (I can count on one hand the number of people I've seen deadlift in my gym over 2 years; ok, that's true only if I exclude the Crossfitters, otherwise I would need two hands). Nevertheless, data from longitudinal studies in athletes suggests that increases in bone density are indeed related to training, suggesting that the above plot isn't entirely correlational.

Oh, and the forces on the lumbar spine during the conventional deadlift? No surprise, they are huge, and the worse your form, the more force you are exposing your spine to. Calculated loads for competitive powerlifters exceed 20 kilonewtons. Climbers will recognize that this is close to the rated strength of many carabiners.

The Evolutionary Search for Our Perfect Past

A thoughtful essay by Marlene Zuk in the NYTimes.

Did our cave-dwelling forebears feel nostalgia for the days before they were bipedal? Were hunter-gatherers convinced that swiping a gazelle from a lion was superior to that newfangled business of running it down yourself? And why stop there? Why not long to be aquatic, since life arose in the sea? For that matter, it might be nice to be unicellular: after all, cancer arises because our differentiated tissues run amok. Single cells don’t get cancer.

Reflections on an Oyster

A great post over at Olivia Judson's blog at the NYTimes.

Born to Run? Your Genetic Advantage

Interesting article in today's NYTimes.

A bestiary of RNA

A nice blurb in the NYTimes on The Promise and Power of RNA.

Dynamic stretching

Interesting article in the Times about how static stretching, advocated by gym coaches and trainers the world over, is not only unhelpful but detrimental to performance as well.

They point to a recent UNLV study (Samuel et al 2008) that examined the effects of static stretching versus dynamic stretching (versus no-stretch control) on lower-leg performance.

Preactivity stretching is commonly performed by athletes as part of their warm-up routine. However, the most recent literature questions the effectiveness of preactivity stretching. One limitation of this research is that the stretching duration is not realistic for most athletes. Therefore, the purpose of this study was to determine the effects of a practical duration of acute static and ballistic stretching on vertical jump (VJ), lower-extremity power, and quadriceps and hamstring torque. Twenty-four subjects performed a 5-minute warm-up followed by each of the following three conditions on separate days with order counterbalanced: static stretching, ballistic stretching, or no-stretch control condition. Vertical jump was determined with the Vertec VJ system and was also calculated from the ground-reaction forces collected from a Kistler force plate, which also were used to calculate power. Torque output of the quadriceps and hamstrings was measured through knee extension and flexion on the Biodex System 3 Dynamometer at 60 degrees x s(-1). Data normalized for body weight were analyzed using five separate, 3 (stretch condition) x 2 (gender) analysis-of-variance procedures with repeated measures on the factor of stretch condition. The gender x stretch interaction was not significant for any of the four measures, suggesting that the stretching conditions did not affect men and women differently. The results of this study reveal that static and ballistic stretching did not affect VJ, or torque output for the quadriceps and hamstrings. Despite no adverse effect on VJ, stretching did cause a decrease in lower-extremity power, which was surprising. Because of the mixed results, strength coaches would be better served to use dynamic stretching before activity; this has been consistently supported by the literature.

They find no difference vertical jump or lower-leg torque strength between the conditions, but static stretching led to a larger decrease in power than dynamic (both compared to control). However, the effect, while significant, was small.

The Challenge of Mountaineering ... for Utility Theory

I suspect that there will be fewer than five people who will appreciate this remarkable confluence of interests. Yeah, that probably includes me.


A choice quote:

To illustrate the importance of motives that are unconnected to consumption, I will focus on personal accounts of a specinc activity: mountaineering. Why mountaineering? Admittedly, I examine mountaineering in part because it so obviously is not about pleasure from consumption. Serious mountaineering which I define broadly to include polar exploration - tends to be one unrelenting misery from beginning to end. The reason why mountaineers are so often asked why they climb mountains, and the reason why their explicit answers are so often unilluminating (e.g., Mallory's 'because it is there') is precisely that their reasons don't fit neatly into materialistic notions of human motivation. Dentists, investment bankers, and real estate brokers are rarely asked why they are engaged in these activities (though I suspect that the extent to which they are motivated by material considerations is exaggerated).

Although mountaineering is ideal for illustrating these non-consumption-related motives, it could be argued that, as a pathological activity engaged in by a small number of unusual people, it has little relevance to economics. The descriptions of mountaineering included in this essay will do nothing to dispel such opinions. But, as I argue in the conclusion, the motives that drive mountaineers are also pervasive in the general population in diverse domains of behavior.

If mountaineers aren't very good at answering the 'why' question when it is posed directly, a close reading of the mountaineering literature reveals myriad clues about their motives. In this essay I draw on works by and about mountaineers to illustrate the importance for human behavior of motives that don't directly involve pleasure from consumption.

Grab the full text here. You can also find the last strange intersection of interests here.

Fasting and flying

As seen in the science newswire: new sleep research from Cliff Saper's lab at Harvard suggests a possible mechanism to moderate the effects of jetlag: fast before you fly, and eat (early in the day) when you get to your destination. They examined which parts of the circadian circuitry in the brain controls light-entrainable versus food-entrainable circadian rhythmicity, focusing on the hypothalamus:



Using knockout mice carrying a deletion of the clock gene Bma1, which lack circadian rhythmicity, they restored Bma1 function to specific hypothalamic nuclei using viral vector injection and show that different brain regions control light (suprachiasmatic nuclei) and food (dorsomedial hypothalamic nucleus) entrainable rhythmicity.

Figure 2 from Fuller et al. 2008. Mice heterozygous for Bma1 show normal food entrainment (A), seen as a rise in body temperature before feeding (gray bar), as well as light entrainment, seen as elevated body temperature during the presumptive dark cycle (12-24h). Both types of rhythmicity are abolished in -/- mice (B), but reintroduction of Bma1 to the DMH restores the preprandial increase in body temperature (C).

The general idea is that fasting induces a state where food consumption is prioritized, causing the body to entrain to periods of food availability. In the authors' words:

For a small mammal, finding food on a daily basis is a critical mission. Even a few days of starvation, a common threat in natural environments, may result in death. Hence, it is adaptive for animals to have a secondary "master clock" that can allow the animal to switch its behavioral patterns rapidly after a period of starvation to maximize the opportunity of finding food sources at the same time on following days.

In actuality, the fact that circadian rhythms are entrainable by food availability was already known (see Krieger 1974; more recently Gooley et al 2006 implicated the dorsomedial hypothalamic nucleus in the process), so the idea that fasting can prevent jetlag is newer to the news media than to the field. However, the positive identification of specific brain region control suggests mechanistic sources for the separability of different kinds of circadian entrainment.

15 seconds of pain

Warm-up:
0.5 mi run

47 rounds:
15 seconds run (treadmill, incline=7, speed=8.8 mi/hr)
15 seconds rest

Wanted to do tabata sprints today, but wasn't sure I could avoid killing myself. Instead I opted for a slightly different protocol recently studied by Helgerud and colleagues (2007). It consists of 15 second intervals at 90-95% max heart rate alternating with 15 seconds at ~70% max heart rate. In the paper, people did this for 47 rounds, three times a week for 8 weeks. It produced some nice results when compared to work-matched controls exercising at different intensities:My heart rate was about 195 while working (wore a monitor), and crept up to about 198-200 during the rests. This is just about 95% of my peak heart rate. I didn't follow the protocol exactly as I basically just rested during the second interval. Can't really say I enjoyed this one; certainly wouldn't want to do it three times a week. On the other hand, it is less debilitating than tabata sprints; it's nice to have options.

Carbohydrates and heart disease

Atherogenic dyslipidemia is a lipoprotein profile that predisposes one to cardiovascular disease. Grundy (1997) characterizes it by four markers: 1) a borderline high-risk LDL cholesterol (130 to 159 mg/dL), 2) moderately raised (often high normal) triglycerides (greater than 150 mg/dL), 3) small LDL particles, and 4) low HDL cholesterol (less than 40 mg/dL for men and 50 mg/dL for women). The third marker is due to data indicating that not all LDL particles are atherogenic; a preponderance of small, dense LDL particles (known as a pattern B phenotype) is associated with increased coronary artery disease (Austin et al., 1988). The presence of atherogenic dyslipidemia itself is a marker for metabolic syndrome.

Source:

Ronald Krauss and colleagues have convincingly shown that changes in carbohydrate intake profoundly affects LDL phenotypes (reviewed in Krauss, 2001). The figure below is a nice summary of the basic observation that restricting carbohydrates reduces the incidence of the atherogenic LDL particle pattern. Note especially the apparent continuity of the effect, and the fact that the carbohydrates are not even severely restricted (certainly nowhere near the levels required to induce ketosis). If you have a half hour to spare, you can catch a recent webcast talk by Krauss summarizing the Pathophysiology of Atherogenic Dyslipidemia.

Source: Krauss, 2001

If you want to full scoop on recent research on the relationship between carbohydrates and dyslipidemia and metabolic syndrome, definitely take the time to check out this review article from Jeff Volek and colleagues (it's technically still in press, but you can grab the galley proofs online). It covers a lot of ground, and is well worth the effort.

Dietary carbohydrate restriction induces a unique metabolic state positively affecting atherogenic dyslipidemia, fatty acid partitioning, and metabolic syndrome.

Volek JS, Fernandez ML, Feinman RD, Phinney SD.

Department of Kinesiology, University of Connecticut

Abstract: Abnormal fatty acid metabolism and dyslipidemia play an intimate role in the pathogenesis of metabolic syndrome and cardiovascular diseases. The availability of glucose and insulin predominate as upstream regulatory elements that operate through a collection of transcription factors to partition lipids toward anabolic pathways. The unraveling of the details of these cellular events has proceeded rapidly, but their physiologic relevance to lifestyle modification has been largely ignored. Here we highlight the role of dietary input, specifically carbohydrate intake, in the mechanism of metabolic regulation germane to metabolic syndrome. The key principle is that carbohydrate, directly or indirectly through the effect of insulin, controls the disposition of excess dietary nutrients. Dietary carbohydrate modulates lipolysis, lipoprotein assembly and processing and affects the relation between dietary intake of saturated fat intake and circulating levels. Several of these processes are the subject of intense investigation at the cellular level. We see the need to integrate these cellular mechanisms with results from low-carbohydrate diet trials that have shown reduced cardiovascular risk through improvement in hepatic, intravascular, and peripheral processing of lipoproteins, alterations in fatty acid composition, and reductions in other cardiovascular risk factors, notably inflammation. From the current state of the literature, however, low-carbohydrate diets are grounded in basic metabolic principles and the data suggest that some form of carbohydrate restriction is a candidate to be the preferred dietary strategy for cardiovascular health beyond weight regulation.

PMID: 18396172

Fasting and your body temperature

Fasting slows down your metabolism in order to reduce energy expenditure (Wang et al., 2004), which may be one of the reasons that animals live longer on dietary regimens such as caloric restriction or intermittent fasting (Liu & Walford, 1972; Rikke & Johnson, 2004; Salerian & Saleri, 2006). Under these regimens metabolic slowing manifests itself in a number of ways, usually a reduction in daily activity and a lower body temperature (Rikke et al., 2003; Severinsen & Munch, 1999). Lane and colleagues (1996) showed that caloric restriction in rhesus monkeys results in a rapid reduction in body temperature, and that the reduction endures for the duration of caloric restriction (in this case years).Humans under caloric restriction also exhibit reductions, albeit smaller, in body temperature. Heilbronn and colleagues (2006) randomized subjects into 1 of 4 groups for 6 months: (1) control (weight maintenance diet); (2) calorie restriction (25% calorie restriction of baseline energy requirements); (3) calorie restriction with exercise (12.5% calorie restriction plus 12.5% increase in energy expenditure by structured exercise); and (4) very low-calorie diet (very low-calorie diet [890 kcal/d] until 15% reduction in body weight, followed by a weight maintenance diet).
Group (3) is particularly interesting, showing that even relatively mild caloric restriction (a degree that can easily occur while intermittently fasting) decreases body temperature. So reducing body temperature is a common response to dietary restrictions, and together with decreases in physical activity are the largest contributors to reducing energy expenditures (reductions in basal metabolism occur, but apparently contribute relatively little).

Evidence suggests that the severity of the dietary restriction dictates the degree of temperature reduction. Rats subjected to total starvation versus caloric restriction (75%, which is quite severe) experienced a significantly greater reduction in body temperature for the duration of restriction, with temperatures in both groups normalizing once ad libitum feeding was reinstated (Severinsen & Munch, 1999).
I haven't found any primate data on body temperature under intermittent fasting, but mice exit torpor, which is a reduction in body temperature during inactive parts of the diurnal cycle, when intermittently fed double and triple rations (Rikke et al., 2003; see also Wan et al., 2003 for body temperature reductions under a more conventional alternate day fasting regimen). Presumably, part of this is due to the caloric expenditure associated with digesting a large meal.

The data also suggest, at least in this mouse strain, that when torpor is re-entered during the fast between meals, that the decrease in body temperature is particularly dramatic.

It's tempting to infer that caloric restriction and/or intermittent fasting cause reductions in body temperature which in turn causes the prolonged lifespans associated with both these dietary regimens. However, a recent experiment using genetically-engineered mice clearly shows that this cannot be the whole story. Conti and colleagues (2006) created transgenic mice where the preoptic area of the hypothalamus, which regulates body temperature, was warmer than normal. This tricked the brain into reducing body temperature by roughly half a degree Celsius, within the range attainable by dietary restrictions or meal patterning. These mice lived 10-20% longer than wild-type mice (in the figure black=wild-type, red=mutant).
The increase in lifespan occurred despite the fact that the transgenic mice ate as much as the normal mice, and actually weighed slightly more. These results indicate that a reduction in body temperature can lengthen lifespan independently of caloric restriction or intermittent fasting. It will be interesting to see whether calorically restricting or intermittently fasting these transgenic mice will lead to even longer lifespans.

I suspect that in practice the wide variation in fasting regimens results in wide variation in the magnitude of body temperature reductions. These factors probably interact with variations in the degree to which individual metabolisms react to dietary restrictions and meal patterning. I would venture to guess based on the evidence that people subjecting themselves to more severe caloric restriction or longer fasts (more severe caloric restriction on a local time scale) will experience the greatest reductions in body temperature. It's unclear to me whether this translates to impaired cold tolerance, although some first-hand reports suggest that it might.

From the archives of Science magazine

A remarkable confluence of interests:The second article is a classic by D. MacKay.

Monitoring health by counting heartbeats

It's often the case that high-intensity workouts (like Fran or Tabata sprints) cause your heart rate to skyrocket in order to meet the metabolic demands of active muscle. Remarkably, the flow of blood to active muscles may increase to four or five times that of resting cardiac output. Just as remarkable is the fact that your heart rate will typically drop 40% five minutes after exercise completion. These dramatic changes in heart rate are controlled by the sympathetic and parasympathetic components of the autonomic nervous system; sympathetic activation increases cardiac acceleration, contractility and coronary constriction whereas parasympathetic activation promotes cardiac deceleration and coronary dilation. Your heart rate response to exercise is largely determined by the balance of these two systems.

Being a sucker for numbers, I'm always on the lookout for simple, predictive physiological measures. There are a few based on heart rate that are strongly predictive of mortality and turn out (not surprisingly) to be modifiable by training. The first is resting heart rate, which the American Heart Association suggests should be between 60-80 beats per minute (bpm). A fast heart rate is associated with an increased risk of death from cardiovascular as well as noncardiovascular causes (Hjalmarson, 2007; Palatini, 1999). Even within the recommended range (60-80 bpm), a lower resting heart rate is significantly associated with decreased risk of dying from any cause, especially heart attack (Jouven et al., 2005).

The second measure is heart rate reserve, the difference between maximal heart rate and resting heart rate. A smaller dynamic range is associated with increased risk of death from any cause, especially heart attack (Jouven et al., 2005), and a failure to reach predicted peak heart rates during graded exercise is predictive of increased mortality and coronary heart disease incidence (Lauer et al., 1996).

Finally, the last measure is heart rate recovery, the difference between maximal heart rate and heart rate measured some fixed time after cessation of exercise (usually 1 or 2 minutes). The failure to drop at least 30 bpm within 1 minute is associated with increase risk of heart attack. A smaller decrease in heart rate suggests a dysfunction of the parasympathetic system, since the decrease in heart rate immediately following exercise is primarily due to parasympathetic reactivation (Imai et al., 1994; Raymond, 2004).

The above figure bins together all the data below 25 bpm recovery, but if you look more closely at lower ranges, an association with risk of death is even more apparent. For all you stats geeks, below is a conditional trellis plot (click the figure to see a larger version) that illustrates risk of all-cause mortality as a function of age, fitness, peak heart rate and heart rate recovery (Ishwaran et al., 2004). Age is a binary grouping indicated by the orange bars (left column is younger than 45 yo and the right column is older than 45 yo). Fitness is a categorical variable indicated by the green bars (least fit in the top row proceeding to most fit in the bottom row). Peak heart rate and heart rate recovery (measured 1 minute after ceasing exercise) are plotted for each subject for whichever panel they correspond to (age x fitness). That's five freakin variables!

And just for kicks, the figure to the right plots some data from the last time I did 400 meter sprints. There goes (220-age) as a predictor for my maximal heart rate! There are better ways of estimating maximal heart rate (e.g., see Joe Friel's work).

It's worth pointing out that these heart rate measures are not independent (Jouven et al., 2005); in fact they're highly correlated, suggesting that they may be different measures of the same disorder. And while the mechanism(s) underlying the association of these heart rate measures with increased mortality and heart disease remain unknown, the data are consistent with the idea that autonomic system imbalance predisposes people to life-threatening arrythmias (Jouven et al., 2005).

Aside from their utility for predicting death, these measures are also interesting because they can be modified by training. Following training, heart rate recovery is accelerated (Darr et al., 1988; Imai et al., 1994; Sugawara et al., 2001) and resting heart rate is decreased (Wilmore et al., 2008). Changes to maximal heart rate are less clear, with some evidence for a slight decrease following endurance training (Darr et al., 1988; Wilmore et al., 2008). So if you're bored, or looking for another way to track progress, break out the stopwatch or heart rate monitor and start logging! Indeed, Levine (1997) showed that the total number of heartbeats in a lifetime is remarkably constant across a wide range of variation in mammals.If we take seriously the idea that a human heart is physiologically predetermined to beat ~3 billion times in a lifetime, perhaps it wouldn't hurt to make reducing your resting heart rate an objective.

Intermittent fasting facilitates learning

Several very interesting papers on the physiological changes that may underlie the benefits of intermittent fasting have been published recently. In rodents, intermittent fasting (typically implemented as alternate day fasting) results in numerous physiological changes that are correlated with disease reduction, increased stress resistance, improved insulin sensitivity and upregulation of neuroprotective trophic factors (reviewed by Mattson, 2005; Varady & Hellerstein, 2007). While many IF studies have used relatively short dietary interventions, a recent study by Fontán-Lozano and colleagues (2007) highlights the intriguing possibility that long-term intermittent fasting can lead to improved cognitive function. In a nice series of experiments, these authors demonstrate that fasted mice exhibit improved learning and memory compared to controls (fed ad libitum), and they go on to provide evidence for the underlying mechanism for this cognitive improvement.

Fontán-Lozano et al. mice placed on an alternate day fasting (ADF) regimen for 6-8 months (starting post-natal week 9, the average lifespan of a mouse is about 2 years). Mice on an ADF diet will typically eat more food on their feed days to compensate for the fasting day, and after some adjustment period will eat a bit less than twice as much food on their feed day as a normal mouse would on an typical diet. So in addition to fasting every other day, there is usually some mild caloric restriction involved. It's well-documented that ADF mice live longer than controls.



Survival distributions (n=40) of male C57BL/6J mice fed ad libitum (left curve) or every other day (ADF, right shifted curve). Souce: Talan & Ingram, 1985




ADF mice will also typically weigh less than control mice (Anson et al., 2003), although the ADF mice in Fontán-Lozano et al.'s experiments weighed the same as control mice. This might be due to the longer time spent on the ADF diet, although there are mouse strain differences in addition to diet duration differences (Goodrick et al., 1990). Fontán-Lozano et al. used a simple battery of behavioral tests to assess the learning and memory capacities of ADF mice. They found that compared to control mice, ADF mice learned faster (in a motor learning task, operant food reward task, and Pavlovian eyeblink conditioning task) and were better able to discriminate novel from familiar objects from briefer presentations.

Subsequent physiological experiments revealed that ADF mice exhibited increased theta-band activity in the hippocampus. Explorations of synaptic plasticity revealed that ADF mice exhibited enhanced paired-pulse facilitation at the CA3-CA1 synapse. Moreover, LTP could be elicited at the Schaffer's collateral–CA1 synapse using fewer high-frequency stimulations. These results are interesting since it is a well-accepted hypothesis that learning and memory are based on modifications of synaptic strength among neurons, an idea that goes at least back to Donald Hebb (1949).

A possible mechanism for the observed potentiation of synaptic plasticity is suggested by the observation that ADF mice also show changes in NMDA receptor subunit composition; this glutamate receptor is critical for many types of synaptic plasticity, and various isoforms exist which are composed of different protein subunits. It's known that the relative expression of NR2B subunits change over the course of a rodent's life; the fraction of NR2B subunits declines (and NR2A increases) in adulthood (Moyner et al., 1994). Fontán-Lozano et al. noted increased expression of NR2B NDMAR subunits in the hippocampus and perirhinal cortex of ADF mice.

Photomicrographs and immunohistochemical analyses of the NR2B expression pattern in the hippocampus of IFD (ADF) and control (ad libitum, AL) mice. The graphs represent the densitometric analysis of NR2B expression in the different areas of hippocampus (n = 5 animals per group in all tests). s luc, Stratum lucidum; mol, molecular layer; l mol, lacunosum moleculare layer; Molec, molecular layer; Lac mol, lacunosum moleculare layer; O.D., optical density. ***p ≤ 0.001. Source: Fontán-Lozano et al., 2007

Remarkably, the behavioral improvements as well as the synaptic enhancements seen in ADF mice are returned to control levels when these mice are administered a NR2B antagonist, which strongly suggests that the relative increase in NR2B subunit expression is responsible for arresting the cognitive decline that accompanies natural aging. This is reminiscent of the genetically-engineered smart mice created by Joe Tsien's group (Tang et al., 1999).

The causal mechanisms underlying the changes in NR2B expression are still unknown. Interestingly, exercise increases NR2B subunit expression in the hippocampus (Farmer et al., 2004), and there is some evidence that ADF can increase basal levels of activity (Carlson & Hoelzel, 1946). Whether there is a link between fasting-induced increases in activity and NR2B subunit expression is an important question for future research.

One thing to keep in mind is that enhanced synaptic plasticity may not necessarily be a good thing. Presumably, there was some selective pressure that led to downregulating NR2B subunit expression with age. It's not clear what this might be, but it may turn out that increased NR2B subunit expression is actually maladaptive once we figure out what the selective pressure was (is, it may still be acting?).

Get fat!

Good fats of course, those being ω-3 fatty acids (a type of polyunsaturated fatty acid [PUFA], another being the ω-6 fatty acids; these are also referred to as n-3 and n-6 fatty acids). Members of these families are derived from the essential fatty acids linoleate (LA) and α-linolenate (LNA). Strictly speaking, these two are the only essential fatty acids (required through diet), although that term is often extended to the entire family of PUFAs (Cunnane, 2003). The ω-3 and ω-6 fatty acids are critical for a host of bodily functions, which you can read about in reviews by Das (2006) and Wijendran and Hayes (2004). Very roughly speaking ω-6 fatty acids are pro-inflammatory whereas ω-3 fatty acids are anti-inflammatory. More specifically, the ω-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are antithrombotic and antiarryhthmic, and dietary intake of these fatty acids is associated with reduced risk of death from cardiovascular disease.

Source: Mozaffarian and Rimm 2006.

Although current evidence indicates that the relative dietary ratios of ω-3 and ω-6 fatty acids is a indicator for overall health (Wijendran and Hayes 2004; Simopoulos, 2002), the mechanisms by which EPA and DHA reduce the risk of cardiac mortality remain unclear. The assumption is that direct incorporation of these fatty acids into the myocardium of the heart underlies their health benefits. That dietary intake directly modulates myocardial phospholipid profile was recently documented by Metcalf et al. (2007). The authors examined the atrial tissue of people undergoing elective cardiac surgery following varying durations of dietary supplementation with fish oil (6 g EPA+DHA/day, for 7-60 days). They found that fish oil supplementation increased the amount of EPA and DHA in the cell membranes of both atrial tissue as well as red blood cells.


It has been proposed that the cardioprotective effects of EPA and DHA result from replacement of arachidonic acid (AA) in cardiac membranes. AA is a precursor of a wide array of eicosanoids (Funk, 2001). These compounds promote inflammatory responses, platelet aggregation, and vasoconstriction. Although these are essential metabolic functions, excess AA-derived eicosanoids can promote atherosclerotic disease and thrombosis.

Source: Calder 2006.

Metcalf et al. also showed that dietary fish oil supplementation reduced atrial AA concentrations, consistent with the idea that part of the benefit of EPA and DHA may be due to the reduction in AA-derived pro-inflammatory factors.


These phosphospholipid adaptations in atrial tissue may thus underlie the cardioprotective effects of dietary fish oil. In support of this, the timescale and magnitude of these changes is broadly consistent with the observation that the protective effects of ω-3 fatty acid supplementation begin early, but reach significance only after about three months.

Source: Marchioli et al. 2002.

Also of note is the fact that supplementing with flaxseed oil (high in ALA) did not result in any changes in ω-3 fatty acid concentrations. This is likely due to the fact that dietary ALA is converted to EPA and DHA at extremely low rates (Plourde & Cunnane 2007), which is consistent with suggestions that ALA supplementation is not cardioprotective (Matthan et al. 2005; Wang et al. 2006).

Running is in our DNA

Running is in our DNA is Asics' new ad campaign slogan. Much better than Reebok's Run easy campaign. I found the ads surfing around for information after the Chicago marathon was cancelled midway through due to heat. Came across a few forum threads about how endurance running was counter to our evolutionary past and how we should only ever sprint. Honestly, most of these sounded like people looking for excuses not to run, but there were a few thought-provokers.

"Humans were just not designed to work for extended periods of time at 80-90% VO2max. Our evolutionary blueprint, the last draft of which was completed well over 10,000 years ago, set us up as great slow-movers and occasional fast sprinters. Our two primary energy systems are: (1) fat-based, which allows for long slow steady walking across the Savannah (or the Queen K after dark); and (2) ATP-based, which gave our ancestors 20 seconds of balls-out sprint speed to escape the charging saber tooth tiger (or let grandma lift the '67 Ford truck off gramps when the jack failed). We just weren't designed to operate at high revs for long periods of time. Doesn’t mean we can't, we can, but it's at an appreciable cost that I will explain shortly. It just means we weren't evolved to. Even our hunter-gatherer ancestors probably relied more on superior tracking skills and walking than they did running for hours or days after their prey. In fact, the energy costs of doing the latter were so high as to almost guarantee extinction."

This quote comes from an interesting piece that Mark Sisson wrote earlier this year. It's worth a read, and I think the argument he makes that chronic high-level training is bad for you is sound. It does, however, raise the interesting question of how endurance running factored into our evolutionary past. I've previously posted a review by Bramble and Lieberman that nicely summarizes the biomechanical and energetic evidence supporting the hypothesis that humans evolved for endurance running (we're pretty slow sprinters as well, relative to the rest of the animal kingdom). Bramble and Lieberman provide some good arguments against the idea that endurance running is simply a by-product of enhanced walking capabilities (see also this paper about what your ass muscles are for).

If not a by-product of walking, then what pressured the evolution of the numerous adaptations for endurance running? In 1984, David Carrier proposed that endurance running evolved to allow early hominids to run their prey to exhaustion, referred to as persistence hunting. Over time, the need for this declined as early humans developed more advanced hunting methods and tools (e.g., arrows), which is perhaps why modern hunter-gatherers rarely engage in endurance running. However, while rare, persistence hunting has been documented in modern hunter-gatherers (reviewed recently by Liebenberg). Persistence hunts covering 20-30 km (~10-20 mi) at average speeds of ~6 km/hour (~3.75 mi/hr) have been documented. This video shows a persistence hunt (from the BBC's Life of Mammals, higher quality version here):The pace is not continuous, but more akin to a fartlek. If I have time, I'll post later on energy systems use in this kind of effort, with some interesting data on marathon running.

To the future:

Elite marathoners giving Fair Chase.

An excellent post on persistence hunting can be found here.

The running man, revisited by Maywa Montenegro (Seed magazine).

The painful truth about trainers: Are running shoes a waste of money? by Christopher McDougall.

Wiggling their toes at the shoe giants by Amy Cortese.

Nut fats

In case you were wondering about the fat profile of nuts (I was cause I just ate 600 calories of cashews):

Source

Turning back the clock

Figure 1 from a recent paper by Melov et al. (2007) studying gene expression profiles in older adults following resistance training. This figure is not particularly useful, and I included because it looks cool (hmmmm). Don't worry though, the results are actually pretty interesting. Melov et al. were interested in how resistance training alters gene expression profiles in skeletal muscle, and whether any of these changes were consistent with a reversal of age-related muscular impairments. They used microarray technology to map the transcription profiles in skeletal muscle of older adults (~70yo) before and after 6 months of full-body resistance training. Perhaps unsurprisingly, a bunch of genes are differentially expressed when older untrained adults are compared to sedentary younger adults, including some associated with mitochondrial function (see also Zahn et al., 2006). However, after 6 months of resistance training (which resulted in significant strength gains), the gene expression profile for older adults was markedly different. A subset of the genes that showed an age-related difference also showed a change in expression due to exercise. Notably, those genes that were expressed at a level lower than young adults were upregulated while those genes that were expressed at a level higher than young adults were downregulated. As the authors put it, the transcriptional signature of aging was reversed back to that of younger levels. Now, I don't have a good sense of how to interpret expression levels, and the authors tended to plot their data on relative scales, so I can't assess the magnitude of these results, but it's an interesting application of gene profiling technology. Unfortunately, there was no individual level correlation of strength gains with changes in gene expression profile (in those genes significantly associated with age and exercise), although this may be a power issue (I guess people aren't jumping for the chance to get repeated muscle biopsies with a 5mm diameter needle!?).

Melov S, Tarnopolsky MA, Beckman K, Felkey K, Hubbard A (2007) Resistance Exercise Reverses Aging in Human Skeletal Muscle. PLoS ONE 2(5): e465 doi:10.1371/journal.pone.0000465

Zahn JM, Sonu R, Vogel H, Crane E, Mazan-Mamczarz K, et al. (2006) Transcriptional Profiling of Aging in Human Muscle Reveals a Common Aging Signature. PLoS Genet 2(7): e115 doi:10.1371/journal.pgen.0020115