Saturday, July 19, 2014

Is the response to calorie restriction purposeful? A challenge to life history theory

I submitted the following article to a scientific journal that specializes in the study of aging, but unfortunately, they rejected it. This is my attempt to grapple with a seeming contradiction between life history theory and the physiological response to calorie restriction. Despite the rejection, I still think the paper and the ideas in it have merit; at this point, the study of aging has too many contradictions, and the field needs to be congruent with the theory of evolution.

Life history theory attempts to understand how organisms allocate their limited resources among growth, reproduction, mating effort, and parental investment.1 These allocations are determined by natural selection so as to provide for the greatest inclusive fitness, including the largest number of viable offspring, given the conditions in which the organism lives. Organisms also change their resource allocations according to environmental signals, such as presence or absence of food and predators, or temperature differences.

Life history theory has postulated that organisms exist along a spectrum that is either r-selected or K-selected. In the former, organisms are oriented towards producing large numbers of offspring with little parental investment; fish, for example, are archetypes of r-selection, producing vast numbers of fertile eggs, and having no role in raising the offspring. In K-selection, organisms produce fewer offspring but with larger parental investment; the offspring may take a relatively long time to mature, and males (fathers) may play a role in raising them. Humans are perhaps the archetype of K-selection.

The theory predicts that certain environmental conditions will cause the organism to shift its strategies for growth and reproduction. For example, abundant food or its opposite, famine conditions, may do this, reproduction being postponed when little food is available. It’s been shown that human females attain menarche at an earlier age when a stepfather lives in the household; age of menarche is also related to the degree of polygyny in a society.2 Thus humans (and other organisms) adjust their life histories to attempt to attain the most advantageous reproductive strategies.

Calorie restriction (CR), and CR mimetics, such as resveratrol and metformin, extend lifespan. The means through which CR and its mimetics do this have been much researched and debated. It does not appear to be the case that CR extends lifespan through limitation of damage by reactive oxygen species, since in many cases antioxidants negate the effects of CR mimetics; the opposite appears to be the case, namely that reactive oxygen species are required for lifespan extension.3 Metformin has been shown to increase the production of reactive oxygen species as at least one mechanism of action.4

The question arises whether an organism’s response to CR is a purposeful response, or whether it is merely something that happens when not enough food is available. Life history theory would predict that the response is purposeful, since fewer nutrients ingested signals a significant environmental deterioration, and the organism may well need to adjust its life history strategy in response. For example, it would make sense to postpone reproduction in the face of less food, since parent or offspring may not be well-nourished, with both having diminished odds of survival. Indeed, reduction of fertility is one response to CR.

However, the notion that the response to CR on the part of an organism is deliberate or purposeful gives rise to a number of paradoxes, which have been well-described by Blagosklonny.5 In the case of declining fertility in the face of CR, the allocation resource paradox would seem the most relevant. Allocating resources to anti-aging repair in the face of famine conditions is likened to moving into a new, luxury apartment in the face of losing one’s job. It seems paradoxical for an organism to allocate resources to a process, anti-aging repair, that it can do wholly without in the face of abundant nutritive resources. Blagosklonny states explicitly, “CR extends lifespan not for any purpose, not in order to live longer. Simply, TOR, which is stimulated by nutrients, drives both growth and aging.”5

Theories of the causes of aging are many. One hypothesis, that elucidated by Blagosklonny, posits that aging is a “quasi-program”, a latent development of the growth program.6 This can account for the effects of CR on aging, since it is the effect of CR and its mimetics on mTOR and other growth pathways, notably the insulin/IGF-1 pathway, that accounts for their lifespan-extending effect. CR, by causing a halt to the growth program, also calls a halt to the quasi-program of aging. Blagosklonny asserts that this hypothesis can account for the various paradoxes of aging, including that of the allocation of resources. The resolution to this paradox lies in the fact that no resources are actually allocated, so the idea that this occurs during times when resources are in short supply becomes moot; all that actually happens is that growth ceases, and with it, aging.

Other theories of the causes of aging, such as that of accumulation of molecular damage by reactive oxygen species, do not seem to be able to resolve the many paradoxes of aging. For example, the lifespan-extending effects of hormesis seem to work by causing damage, with the subsequent upgrading of stress-response mechanisms. So here we have a case where damage supposedly both helps and harms an organism.

As has been stated above, life history theory predicts that organisms will adjust their life history in response to environmental signals, such as lack of food. Now, the adjustments in life history that an organism makes must have a biological basis. For example, earlier puberty is caused by variations in amount and timing of hormones. In this particular case, growth (maturity) has accelerated in order to promote a more optimal life history, i.e. greater inclusive fitness, including greater numbers of viable offspring. The acceleration of growth will presumably, if the quasi-program theory of aging is correct, also mean accelerated aging.

But what would be the proximal biological mechanism through which an organism adjusts its life history program in the face of lack of food? In fact, the response to CR looks like just such a mechanism. The cessation of fertility while food is restricted, for example, bears the mark of an adjustment to life history. Similarly, a decrease in IGF-1, a growth factor, means that the organism will cease growth during food shortage, which is what life history theory would predict. Calorie-restricted humans have reported a drop in sex drive, and CR does in fact result in lower levels of sex hormones. Again, life history theory would predict this. These are examples of phenotypic plasticity, which life history makes use of to adjust strategies among growth, reproduction, and mating effort.

Watve and Yajnik have suggested that growth, as manifested in insulin resistance (IR), may be a physiological mechanism that causes a switch to a more K-selected life history.7 In this theory, gestational insulin resistance causes a greater investment in offspring, since the placenta is relatively less dependent on insulin than other tissues; IR also has a negative effect on ovulation, so fewer offspring will be produced. They also show that IR could be of advantage in younger people, with more nutrients going to the brain, and that actual pathology may only be important at older ages, when natural selection is weaker.

This gives rise to another paradox. The organismal response to CR, whether or not it is indeed deliberate and purposeful, resembles a shift to a more K-selected life history, with fewer offspring, less mating effort, and longer life. But IR, as we saw above, has also been postulated to cause a switch to K-selection. The paradox here is that both more and less food would cause a switch to K-selection. However, if IR is mere pathology, and not a life history switching mechanism, then no paradox arises.

However, IR also accelerates aging. It could even be said that metabolic diseases such as diabetes are archetypes of aging, with high levels of oxidative stress, inflammation, and mitochondrial dysfunction, which are all characteristic of aging. But K-selection involves greater parental investment in offspring, which also implies longer life. Between species, more K-selected organisms live longer than r-selected. In humans, short people, i.e those who experience less growth, live longer.8 Lower levels of growth hormone are associated with less cancer, which is a disease associated with aging.9 So it seems doubtful that IR is anything more than mere pathology, or at least, that its main purpose is to act as a life history switch.

The main paradox that arises here is whether the response of organisms to CR is a deliberate, purposeful one or not. Since life history theory, a main component of the theory of evolution, predicts that organisms will respond to various features of their environment with a change in life history, and since lack of food is a crucial environmental component impinging on survival and reproduction, we would expect that the physiological response to CR is part of the process of a change in life history. On the other hand, if the organismal response to CR is not deliberate or purposeful, but merely what happens when the developmental program of growth is throttled back, then life history theory may need adjustment. For it seems that responding to a lack of food in the environment would be a main function of strategy in life history. An organism must alter its life history when the environment changes in such a crucial way.

Evidence that may resolve the conundrum between life history theory and CR is that coming from studies of intermittent fasting (IF). Most studies of IF have shown that it results in most of the same beneficial effects against aging as does CR, even when experimental animals or humans ingest the same amount of calories as ad lib fed animals or humans. It seems doubtful that deliberate, purposeful changes in physiology accompanied by a switch in life history would come about as a result of the absence of food for a few hours up to one day, since such absences must have commonly occurred during the course of evolution, at least in larger animals. (As well as some individual animals, which might be unable to hunt or forage due to an injury, or bad weather, for example.)
Yet IF also presents us with the notion that halting the growth program of mTOR and related systems periodically for a mere few hours at a time also calls a halt to aging. On theoretical grounds, growth and development, on the one hand, and aging, on the other, would have to be intimately linked indeed.

Moreover, the physiological changes that occur in CR and IF result in organisms that appear much younger than ad lib fed animals, even when CR or IF is initiated relatively late in an animal’s life. This looks not like a mere halt in the quasi-program of aging, but its reversal, which would lend some evidence to it being a purposeful change in life history.

(The author wishes to thank Professor Bruce G. Charlton for his comments on a previous version of the manuscript.)

1. Fabian, D. & Flatt, T. (2012) Life History Evolution. Nature Education Knowledge 3(10):24
2. Kanazawa, Satoshi. "Why father absence might precipitate early menarche: The role of polygyny." Evolution and Human Behavior 22.5 (2001): 329-334.
3. Ristow, Michael, and Sebastian Schmeisser. "Extending life span by increasing oxidative stress." Free Radical Biology and Medicine 51.2 (2011): 327-336.
4. De Haes, Wouter, et al. "Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2." Proceedings of the National Academy of Sciences(2014): 201321776.
5. Blagosklonny, Mikhail V. "Paradoxes of aging." CELL CYCLE-LANDES BIOSCIENCE- 6.24 (2007): 2997.
6. Blagosklonny, Mikhail V. "Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition." Cell Cycle 5.18 (2006): 2087-2102.
7. Watve, Milind G., and Chittaranjan S. Yajnik. "Evolutionary origins of insulin resistance: a behavioral switch hypothesis." BMC Evolutionary Biology 7.1 (2007): 61.
8. He, Qimei, et al. "Shorter Men Live Longer: Association of Height with Longevity and FOXO3 Genotype in American Men of Japanese Ancestry." PloS One 9.5 (2014): e94385.
9. Guevara-Aguirre, Jaime, et al. "Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans." Science Translational Medicine 3.70 (2011): 70ra13-70ra13.

Wednesday, July 16, 2014

Vitamin C improves physical activity levels, reduces incidence and duration of common cold

Vitamin C Supplementation Slightly Improves Physical Activity Levels and Reduces Cold Incidence in Men with Marginal Vitamin C Status: A Randomized Controlled Trial
The early indications of vitamin C deficiency are unremarkable (fatigue, malaise, depression) and may manifest as a reduced desire to be physically active; moreover, hypovitaminosis C may be associated with increased cold duration and severity. This study examined the impact of vitamin C on physical activity and respiratory tract infections during the peak of the cold season. Healthy non-smoking adult men (18-35 years; BMI < 34 kg/m2; plasma vitamin C < 45 µmol/L) received either 1000 mg of vitamin C daily (n = 15) or placebo (n = 13) in a randomized, double-blind, eight-week trial. All participants completed the Wisconsin Upper Respiratory Symptom Survey-21 daily and the Godin Leisure-Time Exercise Questionnaire weekly. In the final two weeks of the trial, the physical activity score rose modestly for the vitamin C group vs. placebo after adjusting for baseline values: +39.6% (95% CI [-4.5,83.7]; p = 0.10). The number of participants reporting cold episodes was 7 and 11 for the vitamin C and placebo groups respectively during the eight-week trial (RR = 0.55; 95% CI [0.33,0.94]; p = 0.04) and cold duration was reduced 59% in the vitamin C versus placebo groups (-3.2 days; 95% CI [-7.0,0.6]; p = 0.06). These data suggest measurable health advantages associated with vitamin C supplementation in a population with adequate-to-low vitamin C status.
NB, these were young men who had marginal vitamin C deficiency. However, physical activity levels were not really only "slightly increased", since by week 7-8 of the trial, they were up by ~40%. Also noteworthy, the researchers state that about 22% of US adults have below adequate C status - and this assumes that that status is properly defined, which it may not be; i.e. lots more people could be vitamin C insufficient. Also, vitamin C blood concentrations were inversely and strongly related to BMI and fat mass.

Despite what the mainstream may tell you, it looks like vitamin C supplementation is far from useless, it may spare people from colds, and could also help weight loss by increasing physical activity.

Monday, June 23, 2014

E-book erratum

A reader pointed out an error in my e-book, "Best Supplements...". On p. 36, the dose for resveratrol should be 2 mg per kg body weight. I had it listed correctly on the previous page, but then misstated it. So if you've downloaded it, please note the correction.

Saturday, June 21, 2014

Bioavailability of Magnesium Salts

Bioavailability of Magnesium Salts – A Review
Background: Magnesium supplementation is of value in several different medical disorders. Several kinds of Mg-salts are commercially available.

Purpose: This review evaluates their bioavailability criteria such as solubility, urinary excretion, and plasma levels of magnesium from studies of different Mg-salts.

Conclusion: Although methodology differences were large, the results consistently demonstrate a better bioavailability for Mg-citrate.
I'm posting this mainly because I've stated in a number of places that magnesium citrate is what you want to take for mag supplementation, since it's better absorbed. This review article comes to the same conclusion.

Friday, June 20, 2014

Magnesium improves athletic performance

Magnesium status and the physical performance of volleyball players: effects of magnesium supplementation
The aim of this study was to test the hypothesis that magnesium supplementation influences the physical performance of volleyball players, as the efficacy of this approach remains questionable. Twenty-five professional male volleyball players were assigned randomly to experimental (350 mg Mg · d–1, 4 weeks) and control groups (500 mg maltodextrin · d–1, 4 weeks) maintaining inter-group homogeneity of urinary magnesium. Erythrocyte, plasma and urinary magnesium levels, plasma creatine kinase activity, lactate production, maximal oxygen uptake (VO2 max) and plyometric (squat jump, countermovement jump, countermovement jump with arm swing) and isokinetic (peak torque, potency and total work) performances were evaluated before (T0) and after (T1) supplementation. Levels of erythrocyte and urinary magnesium and creatine kinase activity and VO2 max remained within normal ranges in both groups. Plasma magnesium decreased significantly only within the experimental group. Significant decreases in lactate production and significant increases (of up to 3 cm) in countermovement jump and countermovement jump with arm swing values were detected in the experimental group following magnesium supplementation, but not in the control group at T1. It is concluded that magnesium supplementation improved alactic anaerobic metabolism, even though the players were not magnesium-deficient.
Sounds as if the researchers started out with doubts, but ended up convinced. They state that the players were not deficient at the start, but if they used a simple blood test for that determination, it's not reliable, as blood tests are a poor determinant of overall magnesium status. In any case, performance improved with magnesium.

Monday, June 16, 2014

Supplements for men's health, strength, and virility

You can download a free copy of my new e-book, Best Supplements for Men's Health, Strength, and Virility, here.

Update: I've been informed that there's an error in the book on p. 36. On previous page, I had said resveratrol dose is 2 mg/kg, which is correct, not 20 mg as on p. 36. In process of correction.

Tuesday, June 10, 2014

Core body temperature negatively associated with longevity

Long-term calorie restriction, but not endurance exercise, lowers core body temperature in humans
Reduction of body temperature has been proposed to contribute to the increased lifespan in calorie restricted animals and mice overexpressing the uncoupling protein-2 in hypocretin neurons. However, nothing is known regarding the long-term effects of calorie restriction (CR) with adequate nutrition on body temperature in humans. In this study, 24-hour core body temperature was measured every minute by using ingested telemetric capsules in 24 men and women (mean age 53.7±9.4 yrs) consuming a CR diet for an average of 6 years, 24 age- and sex-matched sedentary (WD) and 24 body fat-matched exercise-trained (EX) volunteers, who were eating Western diets. The CR and EX groups were significantly leaner than the WD group. Energy intake was lower in the CR group (1769±348 kcal/d) than in the WD (2302±668 kcal/d) and EX (2798±760 kcal/d) groups (P<0.0001). Mean 24-hour, day-time and night-time core body temperatures were all significantly lower in the CR group than in the WD and EX groups (P≤0.01). Long-term CR with adequate nutrition in lean and weight-stable healthy humans is associated with a sustained reduction in core body temperature, similar to that found in CR rodents and monkeys. This adaptation is likely due to CR itself, rather than to leanness, and may be involved in slowing the rate of aging.

Below you can see the correlation between body fat percent and core temperature. The article also contains this statement: "In the Baltimore Longitudinal Study of Aging (BLSA) men with a core body temperature below the median lived significantly longer than men with body temperature above the median in the absence of CR [8]."

Monday, June 9, 2014

Exercise inhibits cancer growth

This is an interesting in vitro study of the effect of exercise on inhibiting growth of cancer cells: Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth
Regular physical activity protects against the development of breast and colon cancer, since it reduces the risk of developing these by 25–30%. During exercise, humoral factors are released from the working muscles for endocrinal signaling to other organs. We hypothesized that these myokines mediate some of the inhibitory effects of exercise on mammary cancer cell proliferation. Serum and muscles were collected from mice after an exercise bout. Incubation with exercise-conditioned serum inhibited MCF-7 cell proliferation by 52% and increased caspase activity by 54%. A similar increase in caspase activity was found after incubation of MCF-7 cells with conditioned media from electrically stimulated myotubes. PCR array analysis (CAPM-0838E; SABiosciences) revealed that seven genes were upregulated in the muscles after exercise, and of these oncostatin M (OSM) proved to inhibit MCF-7 proliferation by 42%, increase caspase activity by 46%, and induce apoptosis. Blocking OSM signaling with anti-OSM antibodies reduced the induction of caspase activity by 51%. To verify that OSM was a myokine, we showed that it was significantly upregulated in serum and in three muscles, tibialis cranialis, gastronemius, and soleus, after an exercise bout. In contrast, OSM expression remained unchanged in subcutaneous and visceral adipose tissue, liver, and spleen (mononuclear cells). We conclude that postexercise serum inhibits mammary cancer cell proliferation and induces apoptosis of these cells. We suggest that one or more myokines secreted from working muscles may be mediating this effect and that OSM is a possible candidate. These findings emphasize that role of physical activity in cancer treatment, showing a direct link between exercise-induced humoral factors and decreased tumor cell growth.
Study shows that a humoral factor is involved, that is, a chemical - a cytokine - released into general circulation by skeletal muscle. To me this also suggests that weightlifting / bodybuilding may be the most effective form of exercise for preventing or stopping cancer, since more weightlifting leads to more muscle, and the muscle will secrete more of the cytokine responsible. That would depend, however, on the best way to produce the cytokine, for instance higher intensity vs greater volume of exercise. But just the fact that weightlifting involves virtually all the muscles in the body suggests that it will be better than endurance exercise for the purpose of preventing cancer.

Wednesday, May 28, 2014

Low-carb diet does not compromise strength and power

In my humble opinion, this study needs to be read and understood by all those people who claim that dietary carbohydrates are necessary for athletics of any kind: Effects of a short-term carbohydrate-restricted diet on strength and power performance
The purpose of the study was to examine the effects of switching from a habitual diet to a carbohydrate-restricted diet (CRD) on strength and power performance in trained men (n = 16) and women (n = 15). Subjects performed handgrip dynamometry, vertical jump, 1RM bench press and back squat, maximum-repetition bench press, and a 30-second Wingate anaerobic cycling test after consuming a habitual diet (40.7% carbohydrate, 22.2% protein, and 34.4% fat) for 7 days and again after following a CRD (5.4% carbohydrate, 35.1% protein, and 53.6% fat) for 7 days. Before both testing sessions, body weight and composition were examined using bioelectrical impedance analysis. Three 2 × 2 multiple analyses of variance were used to compare performance variables between the habitual diet and CRD. Subjects consumed significantly fewer (p < 0.05) total kilocalories during the CRD (2,156.55 ± 126.7) compared with the habitual diet (2,537.43 ± 99.5). Body mass decreased significantly (p < 0.05). Despite a reduction in body mass, strength and power outputs were maintained for men and women during the CRD. These findings may have implications for sports that use weight classes, and in which strength and power are determinants of success. A CRD may be an alternative method for short-term weight loss without compromising strength and power outputs. The use of a 7-day CRD could replace weight loss methods employing severe dehydration before competition.
Note that calorie consumption spontaneously declined, which is what usually or always happens when carbs are restricted. Weight loss occurred, yet power and strength did not decline, which would indicate that the weight loss was almost entirely fat tissue.

Monday, May 26, 2014

Elevated autophagy may help you live longer

Mitochondria hyperfusion and elevated autophagic activity are key mechanisms for cellular bioenergetic preservation in centenarians
Mitochondria have been considered for long time as important determinants of cell aging because of their role in the production of reactive oxygen species. In this study we investigated the impact of mitochondrial metabolism and biology as determinants of successful aging in primary cultures of fibroblasts isolated from the skin of long living individuals (LLI) (about 100 years old) compared with those from young (about 27 years old) and old (about 75 years old) subjects. We observed that fibroblasts from LLI displayed significantly lower complex I-driven ATP synthesis and higher production of H2O2 in comparison with old subjects. Despite these changes, bioenergetics of these cells appeared to operate normally. This lack of functional consequences was likely due to a compensatory phenomenon at the level of mitochondria, which displayed a maintained supercomplexes organization and an increased mass. This appears to be due to a decreased mitophagy, induced by hyperfused, elongated mitochondria. The overall data indicate that longevity is characterized by a preserved bioenergetic function likely attained by a successful mitochondria remodeling that can compensate for functional defects through an increase in mass, i.e. a sort of mitochondrial "hypertrophy".
In the body of the paper, we read:
Autophagy and its sister event called mitophagy are key cytoprotective mechanisms that allow the selection of altered molecules, e.g. misfolded proteins or proteins undergone oxidative changes, or organelles, e.g. altered mitochondria. In DFs from LLI high levels of H2O2, known to induce autophagy [50] have been detected.
Consistently, these cells were characterized by a higher autophagic capability than the other age groups.
So, the cells from very long-lived people appear to have a heightened capacity for autophagy ("self-eating"), among other things. Fortunately for those who want to live longer, there are several things one can do to enhance autophagy. One is intermittent fasting, which induces profound neuronal autophagy. Calorie restriction and resveratrol promote longevity through induction of autophagy. Exercise: "autophagy can also be induced by exercise and that it is integral to the beneficial metabolic effects of exercise." In short, there are several things one can do so that one's cells may have the characteristics of centenarians' cells.

Saturday, May 24, 2014

Does fish oil decrease lifespan?

A new study found that giving fish oil to mice decreased their lifespan: Dietary supplementation with Lovaza and krill oil shortens the life span of long-lived F1 mice
Marine oils rich in ω-3 polyunsaturated fatty acids have been recommended as a preventive treatment for patients at risk for cardiovascular diseases. These oils also are the third most consumed dietary supplement in the USA. However, evidence for their health benefits is equivocal. We tested the daily, isocaloric administration of krill oil (1.17 g oil/kg diet) and Lovaza (Omacor; 4.40 g/kg diet), a pharmaceutical grade fish oil, beginning at 12 months of age, on the life span and mortality-related pathologies of long-lived, male, B6C3F1 mice. The oils were incorporated into the chemically defined American Institute of Nutrition (AIN)-93 M diet. An equivalent volume of soybean oil was removed. Krill oil was 3 % and Lovaza 11 % of the oil in the diets. When their effects were analyzed together, the marine oils significantly shortened life span by 6.6 % (P = 0.0321; log-rank test) relative to controls. Individually, Lovaza and krill oil non-significantly shortened median life span by 9.8 and 4.7 %, respectively. Lovaza increased the number of enlarged seminal vesicles (7.1-fold). Lovaza and krill oil significantly increased lung tumors (4.1- and 8.2-fold) and hemorrhagic diathesis (3.9- and 3.1-fold). Analysis of serum from treated mice found that Lovaza slightly increased blood urea nitrogen, while krill oil modestly increased bilirubin, triglycerides, and blood glucose levels. Taken together, the results do not support the idea that the consumption of isolated ω-3 fatty acid-rich oils will increase the life span or health of initially healthy individuals.
Seems to me that the important questions are whether the dose given to the mice was reasonable. The authors argue that it was. Hemorrhagic diathesis - bleeding into the peritoneum - appeared to be the main cause of death.

The cross-species scaling factors used to adjust dosages between animals and humans suggest that mice should receive 8 to 12 times the effective human dosage of a drug to account for species-specific pharmacodynamic and pharmacokinetic differences (reviewed in Spindler 2012). The Lovaza dose used here is approximately 9.3 times the recommended human dosage per kilogram body weight. The krill oil dosage is modest in comparison to the dosages used in mouse studies to demonstrate a beneficial effect on serum and hepatic cholesterol and triglyceride levels (Vigerust et al. 2012; Tandy et al. 2009). For example, tumor necrosis factor alpha-transgenic mice fed a high-fat diet containing 5.8 % krill oil (approximately five times the dosage used here) had lower plasma levels of triacylglycerol and cholesterol and higher levels of hepatic mitochondrial and peroxisomal fatty acid β-oxidation and carnitine turnover (Vigerust et al. 2012). High fat-fed mice receiving krill oil at 12.5 g/kg diet (approximately 10 times that used here) had reduced hepatomegaly, hepatic steatosis, triacylglycerols, and cholesterol (Tandy et al. 2009).

Monday, May 19, 2014

Shorter men live longer

Shorter Men Live Longer: Association of Height with Longevity and FOXO3 Genotype in American Men of Japanese Ancestry. (ht: HBD Chick).

To determine the relation between height, FOXO3 genotype and age of death in humans.


Observational study of 8,003 American men of Japanese ancestry from the Honolulu Heart Program/Honolulu-Asia Aging Study (HHP/HAAS), a genetically and culturally homogeneous cohort followed for over 40 years....

A positive association was found between baseline height and all-cause mortality (RR = 1.007; 95% CI 1.003–1.011; P = 0.002) over the follow-up period. Adjustments for possible confounding variables reduced this association only slightly (RR = 1.006; 95% CI 1.002–1.010; P = 0.007). In addition, height was positively associated with all cancer mortality and mortality from cancer unrelated to smoking. ... Comparison of genotypes of a longevity-associated single nucleotide polymorphism in FOXO3 showed that the longevity allele was inversely associated with height. This finding was consistent with prior findings in model organisms of aging. Height was also positively associated with fasting blood insulin level, a risk factor for mortality....


Height in mid-life is positively associated with mortality, with shorter stature predicting longer lifespan. Height was, moreover, associated with fasting insulin level and the longevity genotype of FOXO3, consistent with a mechanistic role for the IIS pathway.
Basically this fits everything we have discovered about the causes of aging. In C. elegans, mutations in insulin signaling cause longer life, as does absence of glucose in diet, as well as calorie restriction. All of these affect insulin levels and/or signaling, cause lower growth, and increased lifespan. It appears with the above study that the effect occurs in humans too. Anything that promotes growth will also promote faster aging and lower lifespan.

Keeping fasting insulin levels low ought to be one lesson here for those desiring a longer life. (Most of you, I presume.) Best way to do this is through a low-carbohydrate diet and regular, vigorous exercise.

Sunday, May 11, 2014

Resveratrol enhances exercise performance

Improvements in skeletal muscle strength and cardiac function induced by resveratrol during exercise training contribute to enhanced exercise performance in rats
Resveratrol, an antioxidant found in red wine, has beneficial effects on cardiac and skeletal muscle function, similar to the effects of endurance exercise training.
Combining resveratrol supplementation with exercise training augments the beneficial effects of exercise alone.
We show that endurance capacity is enhanced in rats whose diet includes resveratrol during a 12 week endurance-training programme.
Increased endurance was associated with increases in skeletal muscle force, cardiac function, and oxidative metabolism.
Our results establish that resveratrol is an effective ergogenic aid that enhances exercise performance over exercise alone.
Abstract  Exercise training (ET) improves endurance capacity by increasing both skeletal muscle mitochondrial number and function, as well as contributing to favourable cardiac remodelling. Interestingly, some of the benefits of regular exercise can also be mimicked by the naturally occurring polyphenol, resveratrol (RESV). However, it is not known whether RESV enhances physiological adaptations to ET. To investigate this, male Wistar rats were randomly assigned to a control chow diet or a chow diet that contained RESV (4 g kg−1 of diet) and subsequently subjected to a programme of progressive treadmill running for 12 weeks. ET-induced improvements in exercise performance were enhanced by 21% (P < 0.001) by the addition of RESV to the diet. In soleus muscle, ET + RESV increased both the twitch (1.8-fold; P < 0.05) and tetanic (1.2-fold; P < 0.05) forces generated during isometric contraction, compared to ET alone. In vivo echocardiography demonstrated that ET + RESV also increased the resting left ventricular ejection fraction by 10% (P < 0.05), and reduced left ventricular wall stress compared to ET alone. These functional changes were accompanied by increased cardiac fatty acid oxidation (1.2-fold; P < 0.05) and favourable changes in cardiac gene expression and signal transduction pathways that optimized the utilization of fatty acids in ET + RESV compared to ET alone. Overall, our findings provide evidence that the capacity for fatty acid oxidation is augmented by the addition of RESV to the diet during ET, and that this may contribute to the improved physical performance of rats following ET.
In other studies, exercise has been shown superior to resveratrol in beneficial metabolic effects. But in combination, resveratrol enhanced the effects of exercise.

Friday, May 9, 2014

A link between testosterone and longevity

A satellite cell-specific knockout of the androgen receptor reveals myostatin as a direct androgen target in skeletal muscle.
Androgens have well-established anabolic actions on skeletal muscle, although the direct effects of the androgen receptor (AR) in muscle remain unclear. ... Thus, muscle AR is involved in fiber-type distribution and force production of the limb muscles, while it is a major determinant of the perineal muscle mass. Surprisingly, myostatin (Mstn), a strong inhibitor of skeletal muscle growth, is one of the most androgen-responsive genes (6-fold reduction in satARKO) through direct transcription activation by the AR. Consequently, muscle hypertrophy in response to androgens is augmented in Mstn-knockout mice. Our finding that androgens induce Mstn signaling to restrain their own anabolic actions has implications for the treatment of muscle wasting disorders.
Myostatin is also known as GDF8, and is homologous with (i.e. very similar to) GDF11. The recently reported experiments in which blood from young mice rejuvenated the old mice which received the transfusions pinpointed GDF11 in the blood as the causative anti-aging factor. GDF11 inhibits neurogenesis, myostatin inhibits muscle growth, so the resemblance begins to make sense. As we see in the above excerpt, androgens such as testosterone (T) cause a huge (6-fold) increase in myostatin gene expression. T essentially inhibits its own anabolic effect - negative feedback inhibition.

So, T increases myostatin, which is homologous with GDF11, a proven longevity promoter. It's also known that higher T levels in older men greatly improves health. Could increased myostatin and/or GDF11 be the reason? It's paradoxical (perhaps) that T both increases muscle mass and increases myostatin, which inhibits muscle growth. However, an increase in myostatin and GDF11 could be the reason that T improves older men's health.

Here's a study on T and mortality: Low Serum Testosterone and Mortality in Male Veterans. Low T veterans had nearly double the mortality risk.

Thursday, May 8, 2014

Has the "Eskimo myth" been "exploded?

Vegan physician Neal Barnard writes in HuffPo: New Study Explodes the 'Eskimo Myth'. The idea is that Eskimos (what happened to 'Inuit"?) have more heart disease than has been recognized and that eating lots of omega-3 fats from fish does not protect them from heart disease.

But Eskimos today eat Western foods, drink plenty of alcohol, have high rates of suicide, and are, in short, living far from the way that their ancestors did. Any study that fails to control for that is a poor one.

It may be true that omega-3 fats do not offer a lot of protection if most other aspects of one's lifestyle are harmful. But there's solid evidence for a protective effect of omega-3: Omega-3 Fatty Acids and Cardiovascular Disease: A Case for Omega-3 Index as a New Risk Factor.
The omega-3 fatty acids (FAs) found in fish and fish oils (eicosapentaenoic and docosahexaenoic acids, EPA and DHA) have been reported to have a variety of beneficial effects in cardiovascular diseases. Ecological and prospective cohort studies as well as randomized, controlled trials have supported the view that the effects of these FAs are clinically-relevant. They operate via several mechanisms, all beginning with the incorporation of EPA and DHA into cell membranes.... In as much as blood levels are a strong reflection of dietary intake, it is proposed that an omega-3 FA biomarker, the omega-3 index (erythrocyte EPA+DHA) be considered at least a marker, if not a risk factor, for coronary heart disease, especially sudden cardiac death. The omega-3 index fulfils many of the requirements for a risk factor including consistent epidemiological evidence, a plausible mechanism of action, a reproducible assay, independence from classical risk factors, modifiability, and most importantly, the demonstration that raising tissue levels will reduce risk for cardiac events. For these and a number of other reasons, the omega-3 index compares very favourably with other risk factors for sudden cardiac death.
See figure below for dramatic evidence of the protective effect of omega-3 fats. The highest quartile of omega-3 index had about 10% the risk of heart attack than the lowest.

Update: Inuit (Eskimo) women had a very high rate of smoking: "Inuit women had the highest smoking rate among the Aboriginal population at 71%." Source. H/T Neil J. Edmonson. It would certainly seem like this has more to do with heart disease and stroke than omega-3 levels.

Saturday, May 3, 2014

Vitamin C supplementation increases physical activity, decreases colds

I thought this study was pretty remarkable in that it was a double-blind, randomized controlled trial, and got solid results. Vitamin C supplementation (1000 mg/d) increased physical activity and reduced cold symptoms in young men with adequate-to-low vitamin C status
Nearly 25% of US adults have below adequate vitamin C status (plasma concentrations <28 µmol/L), and 6% of the adult population is classified as deficient (<11 µmol/L). Poor vitamin C status is underdiagnosed as early indications are unremarkable (fatigue, malaise, depression). Such feelings may manifest as a reduced desire to be physically active; moreover, hypovitaminosis C may be associated with increased cold duration and severity. This double-blind, placebo-controlled, randomized study examined the impact of vitamin C (1000 mg daily) on physical activity (PA) and symptoms of upper respiratory tract infections in men during the peak of the cold season. Consenting adults (23.2±3.6 y; 25.1±3.9 kg/m2; 29.5±8.7 μmol/L) completed the Wisconsin Upper Respiratory Symptom Survey-21 daily and the Godin Leisure-Time Exercise Questionnaire weekly. PA was lower in controls (n=14) over the course of the 8-week trial in comparison to the vitamin C group (n=15) (METs: +5.9±3.2 and +18.2±5.9 kcal· kg-1· wk-1; p=0.046). The overall cold symptom severity score was 4-fold higher for controls versus the vitamin C group (2.4±0.7 and 0.6±0.1; p=0.010). The incidence of colds was also higher in controls as compared to the vitamin C group (2.2±0.7 and 0.3±0.1 colds; p=0.008). These data suggest measurable health advantages associated with moderate vitamin C supplementation in a population with adequate-to-low vitamin C status.
Got that? One of the symptoms of low vitamin C status is fatigue. Probably most people suffering fatigue from low vitamin C have no clue as to what's causing it. (As I documented in my book, lots of common, easily overlooked things can cause fatigue; this makes sense, as without certain essential inputs, whether nutrients or other factors such as sleep and light, the body does not function optimally.)

In the above study, it looks as if physical activity was about 3-fold higher in the C group. As well, they had only about 15% of the number of colds that the control group had. So, if you're feeling fatigued, vitamin C supplementation as 1000 mg/d, which is completely safe and cheap, would be a very reasonable step to take.

This study adds solid support for vitamin C supplementation.

Friday, May 2, 2014

High-cholesterol diet improves immunity?

A Cholesterol-Rich Diet Accelerates Bacteriologic Sterilization in Pulmonary Tuberculosis
Background: Hypocholesterolemia is common among tuberculous patients and is associated with mortality in miliary cases. Some in vitro studies have shown that cholesterol is necessary for the good functioning of macrophages and lymphocytes.

Study objectives: To determine whether a cholesterol-rich diet could accelerate sputum sterilization in patients with pulmonary tuberculosis.

Design: An 8-week follow-up, randomized, controlled trial carried out from March 2001 to January 2002.

Setting: A third-level hospital for respiratory diseases in Mexico City.

Patients and interventions: Adult patients with newly diagnosed pulmonary tuberculosis were hospitalized for 8 weeks and randomly assigned to receive a cholesterol-rich diet (800 mg/d cholesterol [experimental group]) or a normal diet (250 mg/d cholesterol [control group]). All patients received the same four-drug antitubercular regimen (ie, isoniazid, rifampin, pyrazinamide, and ethambutol).

Measurements and results: Every week, a quantitative sputum culture and laboratory tests were done and respiratory symptoms were recorded. Patients in the experimental group (10 patients) and the control group (11 subjects) were HIV-negative and harbored Mycobacterium tuberculosis that was fully sensitive to antitubercular drugs. Sterilization of the sputum culture was achieved faster in the experimental group, as demonstrated either by the percentage of negative culture findings in week 2 (80%; control group, 9%; p = 0.0019) or by the Gehan-Breslow test for Kaplan-Meier curves (p = 0.0037). Likewise, the bacillary population decreased faster (p = 0.0002) in the experimental group. Respiratory symptoms improved in both groups, but sputum production decreased faster in the experimental group (p < 0.05). Laboratory test results did not differ between the groups. Conclusions: A cholesterol-rich diet accelerated the sterilization rate of sputum cultures in pulmonary tuberculosis patients, suggesting that cholesterol should be used as a complementary measure in antitubercular treatment.
It's been speculated, notably by Dr. Uve Ravnskov, a noted skeptic of the cholesterol hypothesis of heart disease, that cholesterol protects against infections. There are good mechanistic reasons for thinking so; this passage from the first link explains:
Cholesterol constitutes up to 30% of the total lipid content in the cell membrane, and participates in the fluidity of this structure.10Consequently, cholesterol is involved in the activity of membrane-bound enzymes and membrane functions such as phagocytosis and cell growth.11In this context, Drabowsky et al12demonstrated that cholesterol content in the cell membrane of human lymphocytes is important for their cytotoxic function. Heiniger and Marshall13found that cholesterol participates in the differentiation and proliferation cycles that convert lymphocytes into cytotoxic cells. Moreover, in a work published by Gatfield and Pieters14a clear derangement of the ability of the macrophage to phagocytase mycobacteria was observed when they were depleted of cholesterol.
In TB patients, low cholesterol is strongly associated with mortality. The above study looks as if it proves a causal connection: more cholesterol, better immunity.

Tuesday, April 29, 2014

Can more dietary protein prevent weight gain? Protein leverage and obesity

Simpson and Raubenheimer, the two scientists who came up with the protein leverage hypothesis of obesity, expound on their ideas in Nature.
The weight of evidence indicates that the primary driver of the obesity epidemic in recent decades has been increased intake, rather than decreased energy expenditure. Not surprisingly, much research has focused on the source of these extra calories, with vigorous debate over whether fats or carbohydrates (especially refined sugar) are the main culprits.

But this approach misses a fundamental point. The obesity problem is best understood not as the result of the overconsumption of a single macronutrient, but from a skewing of the proportion of each macronutrient in our diet — notably the dwindling quantity of protein in processed food products. The paucity of protein relative to fats and carbohydrates in processed foods drives the overconsumption of total energy as our bodies seek to maintain a target level of protein intake.
In essence, foods that are "dilute" in protein make us eat more calories so as to satisfy protein requirements. This study reported that a 1% increase in protein intake was associated with 30 to 50 calorie lower food intake daily.
The range of processed food becoming available is evolving faster than our appetite control systems. Simple sugars and fat were rare in our ancestral environment and highly prized. This may be why modern humans tend to favour the fatty and sugary foods that now surround us, and would also account for the trend in agriculture and industrialization towards producing readily digested carbohydrates and fats.

Populations accustomed to a high-protein diet, such as hunter-gatherers, may be most at risk in moving to a modern diet where protein is in short supply. If their physiology reflects their ancestral diet, they may have appetite systems that strive for an even higher protein intake than populations whose ancestors switched earlier to an agricultural lifestyle with a high-carbohydrate diet.
Protein appears to be the food that produces the most satiety. On that basis, it seems that increasing protein in the diet would be helpful in losing weight. And in fact virtually all of the clinical studies show this.

Monday, April 28, 2014

Intermittent fasting can slow or reverse one aspect of aging

One of the hallmarks of aging is dysfunctional mitochondria - the cells' energy powerhouses. Cells have a built-in mechanism for dealing with dysfunctional mitochondria and other disordered organelles and protein molecules, and that mechanism is autophagy ("self-eating"). In autophagy, selected components of the cell are targeted for degradation and the components recycled. Mitochondria removal by autophagy
Mitochondrial dysfunction has severe cellular consequences and is linked with neurodegenerative diseases and aging. Maintaining a healthy population of mitochondria is thus essential for proper cellular homeostasis. Several strategies have evolved to prevent and limit mitochondria damage, and macroautophagy plays a role in degrading superfluous or severely damaged mitochondria. Selective removal of mitochondria by autophagy (termed mitophagy) has been extensively studied recently in both yeast and mammalian cells. In this review, we summarize our current knowledge of mitophagy. We also compare the molecular process of mitophagy with other types of specific autophagic pathways and discuss its biological importance.
Just as dysfunctional mitochondria increase in aging, unfortunately the autophagy process declines: older people (and animals) are unable to ratchet up the degree of autophagy as much as younger. One reason older organisms have this problem is due to cellular sense mechanisms, which detect changes in amino acid concentration in the blood.

One way to increase autophagy is through intermittent fasting. In this case, the prolonged absence of food, and with it amino acids from proteins, causes the cells to start and/or increase autophagy so as to maintain healthful amino acid levels in the system. Autophagy is activated after several hours of fasting.

So, to help keep highly functioning mitochondria in the cells, fast. An easy way to do this is to eat nothing between dinner one evening and lunch the next day. (Coffee and tea are fine.) This way, only one meal, breakfast, is skipped, and it's pretty easy to do, especially if you already eat low-carb style.

Saturday, April 26, 2014

Omega-3 fights cancer

The following is a study done with cell culture, which shows that DHA, an omega-3 fat, severely messes with cancer cells. Docosahexaenoic acid attenuates breast cancer cell metabolism and the Warburg phenotype by targeting bioenergetic function
Docosahexaenoic acid (DHA; C22:6n−3) depresses mammary carcinoma proliferation and growth in cell culture and in animal models. The current study explored the role of interrupting bioenergetic pathways in BT-474 and MDA-MB-231 breast cancer cell lines representing respiratory and glycolytic phenotypes, respectively and comparing the impacts of DHA with a non-transformed cell line, MCF-10A. Metabolic investigation revealed that DHA supplementation significantly diminished the bioenergetic profile of the malignant cell lines in a dose-dependent manner. DHA enrichment also resulted in decreases in hypoxia-inducible factor (HIF-1α) total protein level and transcriptional activity in the malignant cell lines but not in the non-transformed cell line. Downstream targets of HIF-1α, including glucose transporter 1 (GLUT 1) and lactate dehydrogenase (LDH), were decreased by DHA treatment in the BT-474 cell line, as well as decreases in LDH protein level in the MDA-MB-231 cell line. Glucose uptake, total glucose oxidation, glycolytic metabolism, and lactate production were significantly decreased in response to DHA supplementation; thereby enhancing metabolic injury and decreasing oxidative metabolism. The DHA-induced metabolic changes led to a marked decrease of intracellular ATP levels by 50% in both cancer cell lines, which mediated phosphorylation of metabolic stress marker, AMPK, at Thr172. These findings show that DHA contributes to impaired cancer cell growth and survival by altering cancer cell metabolism, increasing metabolic stress and altering HIF-1α-associated metabolism, while not affecting non-transformed MCF-10A cells. This study provides rationale for enhancement of current cancer prevention models and current therapies by combining them with dietary sources, like DHA.
Supplementing with DHA from fish oil is a good idea and may stop cancer in its tracks.