Happy New Year to our fellow
lovers of life and of freedom.
Live long & prosper!
Rise early. Work late. Strike oil.
— J. Paul Getty
Some people drink from the fountain of knowledge. Others just gargle.
— Robert Anthony
If you keep your mind sufficiently open, people will throw a lot of rubbish into it.
— William A. Orten
Political correctness is a doctrine, fostered by a delusional, illogical minority, and rabidly promoted by an unscrupulous mainstream media, which holds forth the proposition that it is entirely possible to pick up a turd by the clean end.
— R. J. Wiedman LtCol. USMC Ret.
In all very numerous assemblies, of whatever character composed, passion never fails to wrest the sceptre from reason … Had every Athenian citizen been a Socrates, every Athenian assembly would still have been a mob.
— James Madison, Federalist No. 55 (1788)
In “The Future of Western War” the author notes that “unless we submit to genetic engineering, or unless video games have somehow reprogrammed our brains, or UNLESS WE ARE FUNDAMENTALLY CHANGED BY EATING DIFFERENT NUTRIENTS — these are possibilities brought up by so-called peace and conflict resolution theorists — human nature will not change. And if human nature will not change … then war will always be with us.” (emphasis added)
— Victor Davis Hanson, Distinguished Fellow in History, Hillsdale College
(D&S Comment: Data support the notion that human nature can, at least temporarily, be fundamentally changed by eating certain nutrients, such as omega-3 fatty acids or (to increase serotonin) tryptophan or 5-hydroxytryptophan — and this can be all to the good as far as reducing impulsive violent aggression, envy, and vindictiveness, but if your enemies do not do the same, you still better be prepared for war.)
To lay with one hand the power of the government on the property of the citizen, and with the other to bestow it upon favored individuals to aid private enterprises and build up private fortunes, is none the less a robbery because it is done under the forms of law and is called taxation.
— Samuel F. Miller, Supreme Court Justice
writing for the majority in Loan Association v. Topeka, 1874
Excerpts from “How to Make Wealth”
Originally published in May 2004 in Hackers & Painters
If you want to create wealth, it will help to understand what it is. Wealth is not the same thing as money.
Wealth is the stuff we want: food, clothes, houses, cars, gadgets, travel to interesting places, and so on.
But if wealth is the important thing, why does everyone talk about making money? It is a kind of shorthand: money is a way of moving wealth, and in practice they are usually interchangeable. But they are not the same thing, and unless you plan to get rich by counterfeiting, talking about MAKING money can make it harder to understand how to make money.
People think that what a business does is make money. But money is just the intermediate stage — just a shorthand — for whatever people want. What most businesses really do is make wealth. They do something people want.
When those far removed from the creation of wealth — undergraduates, reporters, politicians — hear that the richest 5% of the people have half the total wealth, they tend to think INJUSTICE! An experienced programmer would be more likely to think IS THAT ALL? The top 5% of programmers probably write 99% of the good software.
I think the single biggest problem afflicting large companies is the difficulty of assigning a value to each person’s work.
To get rich you need to get yourself in a situation with two things, measurement and leverage. You need to be in a position where your performance can be measured, or there is no way to get paid more by doing more. And you have to have leverage, in the sense that the decisions you make have a big effect.
But you don’t have to become a CEO or a movie star to be in a situation with measurement and leverage. All you need to do is be part of a small group working on a hard problem.
You can measure the value of the work done by small groups.
A big company is like a giant galley driven by a thousand rowers. Two things keep the speed of the galley down. One is that individual rowers don’t see any result from working harder. The other is that, in a group of a thousand people, the average rower is likely to be pretty average.
Steve Jobs once said that the success or failure of a startup depends on the first ten employees. I agree. If anything, it’s more like the first five. Being small is not, in itself, what makes startups kick butt, but rather that small groups can be select. You don’t want small in the sense of a village, but small in the sense of an all-star team.
Don’t let a ruling class of warriors and politicians squash the entrepreneurs. The same recipe that makes individuals rich makes countries powerful. Let the nerds keep their lunch money, and you rule the world.
Start the New Year With a Hearty Laugh!
A new paper1 reports beneficial effects of a “laughter intervention study” in vascular function of young healthy adults. Researchers were serious when they designed their study to detect possible effects of laughter on vascular function. They first evaluated potential study subjects for their propensity to laugh using a “cheerfulness questionnaire.” Those candidates who marked “strongly disagree” on the questions “Everyday life often gives me the occasion to laugh” and “I like to laugh and do it often” were excluded. This was done to ensure that the subjects who were shown a comedy could be expected to emit mirthful laughter. (Participants were allowed to make their choice of a comedy program from the laboratory’s DVD collection, or they brought their own.)
The results showed that ischemia (induced presumably by contracting a blood pressure cuff around the ankle), resulted in a significant increase in brachial artery flow-mediated vasodilation (as detected by ultrasound imaging) in those watching the comedy (17%) as compared to subjects watching a documentary, who had a brachial artery flow-mediated vasodilation decrease of 15%. Carotid artery compliance (a measure of arterial elasticity) increased significantly by 10% immediately after watching the comedy and returned to baseline 24 hours after the viewing. Carotid artery compliance did not change significantly throughout the documentary viewing. The comedy-induced changes in arterial compliance were found to be significantly associated with baseline flow-mediated dilation; thus, those with a healthier endothelium had greater effects from the mirthful laughter (the psychobiochemical changes associated with the physical and emotional effects of laughter). Note that, like exercise, the effects of laughter were transient.
The documentaries watched by the unlucky subjects who had to watch documentaries were not identified except for two examples given: “Iraq for Sale” and “Wal-Mart: The High Cost of the Low Price.” No wonder those subjects didn’t laugh.
An interesting new study1 shows that exposing mice to dim light during the period when it is normally dark and when they normally eat most of their food results in a shift to more eating during the daytime (light) period and in excess weight gain.
It has already been shown that exposing humans to dim light during the night-time attenuates important biological effects that ordinarily take place after dark, particularly the release of melatonin. Night shift work has been shown to elevate body mass index in humans. 2 In the new study, mice (which are ordinarily active after dark and also do most of their eating at that time) were exposed to a circadian rhythm of light followed by dim light (16 hours light/8 hours of dim light), a standard light/dark cycle (16 hours light/8 hours dark), or continuous light.
Mice housed in either the continuous light or in light followed by dim light had significantly increased body mass and reduced glucose tolerance as compared with mice in a standard light/dark cycle. This was the case despite the fact that the mice in the two conditions had similar levels of total caloric intake and total daily activity! (Perhaps the mice hadn’t read the official FDA pronouncement that weight is determined only by calories and exercise.) The mice in the light/dim light group ate 55.5% of their food during the light phase, as compared to only 36.5% eaten during the light phase by the light/dark mice. In the light/dim light group, the increased body mass could be prevented by feeding the animals only during the dim light period when it would ordinarily be dark and the mice active. Moreover, mice that had their food access limited to the light period (when mice are normally inactive) had increased weight gain whether they were housed in light/dark conditions or were housed in light/dim light but fed only during the light period.
The results showed that dim light at a level as low as 5 lux “is sufficient to uncouple the timing of food consumption and locomotor activity, resulting in metabolic abnormalities.” (Our comment: Your computer monitor or TV is a lot brighter than 5 lux unless you turn the intensity way down.)
A hypothesis: Sandy wondered whether the effects of dim light on night-time eating and physical activity could be prevented or attenuated by taking melatonin earlier in the evening (e.g., after the start of the dark period but earlier than the normal bedtime) so as to induce circadian changes that would normally take place in the dark even when there is dim light present. Durk tried it (n=1) and it does seem to reduce the desire to eat after dark. If you have a night time eating problem, you might try this.
The Unfortunate Result of Poorly Designed Clinical
Trials without Adequate Explanation of Findings
The cardiovascular benefits of omega-3 fatty acids have been well established in several hundred peer reviewed scientific papers, but as some conflicting data continue to be published (unavoidable when study designs and populations studied can greatly differ), there is still some confusion among doctors and the public concerning the use of omega-3 fatty acid supplements. One particularly unfortunate study was published in the Nov. 18, 2010 the New England Journal of Medicine showing that a “low dose” of omega-3 fatty acids “did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infarction …”
The core of the problem with this study was the way the dose of the omega-3 fatty acids was chosen and why it was so low (too low to provide the intended benefits). In fact, how the dose was selected wasn’t even discussed in the paper, but it became all too apparent to us after identifying the source of the omega-3 enriched margarine used in the study. The supplier of the trial margarines was Unilever R&D, as identified at the very end of the paper. Clearly, then, the purpose of the study from Unilever’s point of view was to evaluate the benefits in a clinical trial of an omega-3 fortified margarine they were developing. Nothing wrong with that, of course, but it appears likely that the dose of omega-3 fatty acids added to the margarine had to be restricted to a low dose due to the problem of preventing off-tastes if the dose were higher. As a result, the study tested the effects of a low dose chosen to avoid off-tastes rather than a higher dose more likely to provide the desired benefits to the heart attack patients.
The subjects were 4837 patients who had had a prior heart attack and who were 60–80 years of age, with 78% being men. These patients, who were receiving “state-of-the-art” antihypertensive, antithrombotic, and lipid lowering therapy then received one of four trial margarines: a margarine supplemented with EPA and DHA (with a targeted additional daily intake of 400 mg of EPA-DHA), a margarine supplemented with ALA (alpha linolenic acid (an omega-3 fatty acid which has a shorter carbon chain than DHA and EPA) targeted to deliver 2 grams of ALA a day, a margarine supplemented with EPA-DHA and ALA, and a placebo margarine.
In fact, the subjects ate on average 18.8 grams of margarine a day, which resulted in additional intakes of 226 mg of EPA combined with 150 mg of DHA, 1.9 grams of ALA, or both, in the active treatment groups.
Lower Than the Omega-3 Dose Recommended By the American Heart Association
In the AHA Scientific Statement,2 the authors concluded that “[e]vidence from prospective secondary prevention studies suggests that EPA + DHA supplementation ranging from 0.5 to 1.8 g/d (either as fatty fish or supplements) significantly reduces subsequent cardiac and all-cause mortality.” Hence, the low-dose margarine did not supply even as much of EPA + DHA as the lowest dose in the AHA recommended range. We personally recommend 2 grams of EPA + DHA for most people, and suggest that those at risk for heart attacks ask their doctor if he or she would see a problem with an intake of 4 grams a day of EPA + DHA.
Unfortunately, the media reported this study as a failure of omega-3 fatty acids to provide protection. Despite the negative conclusion, in fact in the subgroup of women receiving the ALA supplemented margarine, there was a reduction in the rate of major cardiovascular events that approached significance (p = 0.07). Moreover, a post hoc exploratory analysis carried out by the authors found that in diabetic patients, “we found reductions in cardiovascular end points with EPA-DHA, as compared with placebo, that were in line with those shown in the GISSI-Prevenzione trial. The strongest effects — reductions of approximately 50% — were the effects on the rates of fatal coronary heart disease and arrhythmia-related events. The rate of arrhythmia-related events was also reduced with ALA as compared with placebo or EPA-DHA only.”
We hope that Unilever and other companies developing omega-3 supplemented margarines do not lose interest as a result of this study but look into the possibility that better stabilized omega-3 fatty acids (such as the purified and deodorized omega-3 fatty acids we offer in our omega-3 formulation) would allow an increased amount of omega-3 to be added to the margarine. We certainly hope that the negative media reports on this study do not discourage doctors from recommending and consumers from taking DHA-EPA supplements.
Anti-aging and Rejuvenating Effects of
Quercetin in Aging and Senescent Fibroblasts
A new paper1 reports intriguing anti-aging effects of quercetin, a polyphenol found ubiquitously in fruits, vegetables, nuts, and plant-derived beverages such as tea and wine.
It has been reported1 that proteasome inhibition accelerates the onset of replicative senescence in human embryonic fibroblast cultures. The proteasome is an important cellular structure that degrades old or faulty (such as oxidized) proteins and also acts to regulate signal transduction by degrading certain signaling molecules after their desired period of activation. “A reduction in proteasome activity has been observed in aged cells of diverse origins and in replicatively senescent cells.”2 The accumulation of oxidized and damaged cellular proteins accompanies the loss of proteasome activity.
In the new paper1 on quercetin, the researchers found quercetin and its fatty derivative, quercetin caprylate, to be potent proteasome activators. Moreover, they found these compounds to have a rejuvenating effect on middle-aged and terminally senescent primary fibroblasts. Young HFL-1 (human embryonic fibroblasts) cells treated continuously with 2 μg/ml of quercetin throughout their lifespan maintained the young morphology longer than the same cells not treated with quercetin. However, as the researchers found that the quercetin had a growth retardation effect on the cultures, they also tested quercetin caprylate to see whether eliminating the growth retardation would impact the effect on youthful morphology. “Indeed, a minimal (less than 5%) but still statistically significant increase of cellular lifespan was scored upon QU-CAP [quercetin caprylate] treatment as compared to their control counterparts …” Cells treated with the two compounds were reported to be more elongated, growing in parallel arrays as compared to the higher number of flattened cells with more irregular shape in the control cultures.
Even more strikingly, when middle aged or terminally senescent cells were treated with quercetin or quercetin caprylate, they exhibited a higher proliferation rate (even the terminally senescent cells, which started with a proliferation rate of 0!). (Middle aged cells were treated with 2 μg/ml quercetin, 0.5, 2 and 5 μg/ml quercetin caprylate or the diluents (0.1% DMSO or 0.1% caprylate) for 5 consecutive days and for two weeks for the terminally senescent cells.) Moreover, the cells displayed a “rejuvenated phenotype” with more elongated morphology and with lower numbers of beta-galactosidase (a marker of senescence) containing cells. Both quercetin and quercetin caprylate improved oxidative resistance in the cells.
Importantly, both quercetin and quercetin caprylate were found to increase CT-L proteasome activity, by about 1.5 fold by quercetin caprylate to about 2.4 fold by quercetin.
We both take quercetin (there are 128 mg of quercetin in the recommended 12 capsules/day dose of our multivitamin multimineral antioxidant high potency formulation).
A new paper1 reports on the ability of quercetin or N-acetylcysteine to prevent disuse muscle atrophy in tail-suspended mice. The problem with this study was the nonphysiological method of treatment administration: the quercetin or N-acetylcysteine or flavone (a natural flavone without antioxidant effects) were administered by injection into the gastrocnemius muscle of one leg of the seven week old male C57BL/6 mice subjected to the tail suspension procedure. Hence, the results are properly stated (as the authors did): “quercetin has the potential to suppress the atrophy of skeletal muscle when concentrated in the target tissue.”1 However, we would expect similar results from taking oral quercetin along with other antioxidant supplements, which could deliver considerable quantities of antioxidants to the muscles.
As the authors explain, oxidative stress is believed to be a major cause of muscle disuse atrophy. The authors themselves carried out another experiment2 in which they found that intragastric supplementation, which should work like oral supplementation, of the amino acid cysteine prevented unloading-induced ubiquitination in association with redox regulation in rat skeletal muscle. Moreover, in experiments “using cultured myotubes, 1 [quercetin] suppressed the expression of atrogin and MuRF-1 [muscle disuse atrophy associated signaling molecules] and the MEK/ERK signaling, a well-known mitogen-activated protein kinase (MAPK) pathway to mediate oxidative stress.”1
Interestingly, although both quercetin and N-acetylcysteine individually suppressed the decrease of muscle weight to whole body weight ratio, quercetin significantly suppressed the induction of atrogin-1 and MuRF-1, while N-acetylcysteine suppressed the induction of atrogin-1, but not the induction of MuRF-1.1 The non-antioxidant flavone had no effect on muscle-weight loss or the expression of ubiquitin ligases.
Both quercetin and N-acetylcysteine prevented the increase in TBARS (a measure of lipid peroxidation, which is increased under conditions of oxidative stress) that occurred in the gastrocnemius muscle of the tail-suspended mice that received no quercetin or N-acetylcysteine.
These results suggest to us that adequate supplementation with quercetin and other antioxidants can reduce or suppress the muscle loss that would otherwise occur under conditions of lack of exercise (disuse atrophy). Exercise has many other beneficial effects besides helping maintain muscle mass, but the latter is probably its most important effect as loss of muscle has such a major impact on physical capabilities at any age. Hence, it is very helpful to be able to prevent or attenuate that loss, at least as far as it comes from disuse atrophy, with antioxidant supplements.
You may assume that your family-associated increased risk of some diseases could have an effect on your likelihood of living a long lifespan. That may not be true, at least as suggested by a recent paper.1 In this study, a set of currently known alleles increasing the risk of coronary artery disease and type 2 diabetes that have been identified by genome-wide association studies were tested for compatibility with human longevity.
In the new study, the researchers showed that “nonagenarian siblings from long-lived families and singletons older than 85 y of age from the general population carry the same number of disease risk alleles as young controls. Longevity in this study population is not compromised by the cumulative effect of this set of risk alleles for common diseases.”
That appears to be good news. However, it is important to remember that regulation of DNA transcription by histones (and, hence, importantly, histone methylation and demethylation) is an important part of gene expression2–4 that would not be detected by identification of alleles alone. Hence, maintenance of appropriate levels of histone methylation and demethylation is an important part of what determines how your DNA eventually plays a role in whether you get diseases that you may be at risk for and how long you live. For a start, you might take (as we do) supplements of methyl-donating nutrients, such as choline (which we get from our sugar-free choline supplement and betaine and folic acid, as well as an important natural enzyme cofactor in the regulation of histone methylation, S-adenosylmethionine (SAMe).5–7
Although high doses of resveratrol in some studies have been shown to extend lifespan in invertebrates and (at high doses, 22 or 186 mg/kg/day) has been shown to improve health and survival in mice fed a high fat diet,1 further work is needed to determine how resveratrol at lower doses, achievable with reasonable resveratrol supplementation would affect aging in mice on a normal (rather than high fat) diet.
A recent paper2 reports the results of just such a study. Male C57BL/6xC3H/He F1 hybrid mice were fed from middle age (14 months) to old age (30 months) with a low dose of resveratrol (4.9 mg/kg/day) or a CR (calorie restricted) diet and examined by genome-wide transcriptional profiles for genetic differences between these two groups and controls (fed the control diet with no supplemental resveratrol). These authors had previously reported that this CR regimen started at middle age in this strain leads to a 13% increase in average and maximum lifespan. As they did in their earlier study, the researchers reported in this study that CR had a large effect in opposing age-related changes: “CR reduced 921 (90%) age-related alterations in gene expression and 536 of these represented highly significant differences (P ≤ 0.01) in expression between the old control and old CR groups.”
The researchers report here that “resveratrol opposed 947 (92%) of age-related changes in gene expression, and 522 of these represented highly significant differences in expression between the old control and old resveratrol groups (P ≤ 0.01). Thus, resveratrol at doses that can be readily achieved through dietary supplementation in humans is as effective as CR in opposing the majority of age-related transcriptional alterations in the aging heart.” For example, the myocardial performance index, an overall assessment of cardiac function, increases significantly with age (reflecting decreasing cardiac function); resveratrol supplementation “almost completely prevented” this age-related change. This mouse dose of resveratrol is very roughly equivalent to a dose of 250 mg/day for an adult human.
Lesser effects on aging changes were found in skeletal muscle. Aging resulted in alteration of expression of 515 skeletal muscle genes, 136 (26%) of which were significantly (P ≤ 0.01) opposed by CR and resveratrol. In the neocortex, CR and resveratrol were reported to significantly inhibit only 19 and 13% respectively of the 505 highly significant age-related changes in gene expression. Both CR and resveratrol supplementation lowered blood glucose levels (P = 0.06 for CR, P = 0.07 for resveratrol). Unlike CR, however, low dose resveratrol did not reduce circulating IGF-1 (insulin-like growth factor-1) levels. Moreover, there was no decrease in the resveratrol-treated mice in spontaneous liver tumors, which were as abundant as in mice on the control diet, but rare in the CR mice.
Surprisingly, in this study, neither CR nor low dose resveratrol supplementation induced the activity of SIRT1, a longevity-associated gene. CR, but not resveratrol, did induce higher activity of PGC-1alpha, a master regulator of mitochondrial biogenesis.
Unfortunately, the researchers were unable to compare the effects of CR and low dose resveratrol on lifespan because the study involved the use of a long-lived strain and, as they killed the mice at 30 months of age, they could not evaluate effects on average or maximum lifespan. It wasn’t explained why all the mice were killed before at least some of them were allowed to live out their lives so as to capture the lifespan results. However, since the incidence of spontaneous liver tumors was decreased by CR but not by resveratrol and since higher circulating IGF-1 levels (reduced by CR but not by resveratrol) are generally considered a risk factor for cancer, it appears to us that the resveratrol supplemented mice may not have lived as long as the CR mice.
Another 2008 paper3 by a different group of researchers (the same group that published paper #1) compared the results of resveratrol supplementation in mice fed a standard diet (not high fat) ad lib versus mice fed every other day (EOD), a type of dietary restriction with similar but not identical effects to CR, calorie restriction. The usual EOD consists of a period (most often 24 hours) of ad lib feeding alternated with a day of fasting.4 In one human EOD study, subjects were allowed a liter of milk and 2–3 pieces of fruit on their “fasting” day.5 As the researchers3 explain. [a]lthough EOD feeding and conventional caloric restriction (reducing daily intake by ~40%, “CR”) share key features, including [in rodents] extending mean and maximum lifespan, preventing age-related disease, and improving insulin sensitivity, they have not been shown to work through a common mechanism.”
The purpose of the study was to determine whether resveratrol could mimic the age retarding effects of EOD. At 1 year of age, the mice were placed on a standard control diet (SD) or EOD feeding with or without resveratrol (low resveratrol was 100 mg/kg of food; high resveratrol was 400 mg/kg of food). (A typical adult human consumes about 500 grams of food per day on a dry weight basis.) They found that the long-term resveratrol treatment slows age-related degeneration and functional decline and mimics the gene expression patterns induced by EOD feeding, but without extending lifespan. For example, they observed reductions of osteoporosis, cataracts, vascular dysfunction, and declines in motor coordination. However, resveratrol did not reduce the incidence of lymphoma, a major cause of mortality in C57BL/6 mice. Another difference was that EOD strongly upregulated glutathione metabolism, whereas resveratrol had no effect. Surprisingly, the effect of resveratrol on SIRT1 in this study was not reported.
“In the context of the standard diet [SD], resveratrol did not increase overall survival or maximum lifespan … EOD feeding produced a trend toward increased longevity compared to the SD control group, but the effect did not reach statistical significance. Our results are consistent with the previous observation that the effect of EOD on longevity is diminished in older C57BL/6 mice, which is also true of DR [dietary restriction] by 40% restriction. Notably, EOD feeding in combination with the lower dose of resveratrol did extend both mean and maximal lifespan by 15% compared to SD controls.”3
A recent study1 reports a remarkable increase in spinal bone mineral density (BMD) in older women (65–75 years old) who took 50 mg/day of oral DHEA (dehydroepiandrosterone) supplements for 1 or 2 years, as compared to those who received placebo. DHEA was co-administered with vitamin D and calcium. (The men in the study, who also received either 50 mg DHEA/day or placebo along with vitamin D and calcium over the same period, did not have any difference in measures of BMD or bone turnover markers between the two groups; both DHEA and placebo groups had spine BMD increases of 1–2%, but that was thought to be due to the Vitamin D and calcium, which was administered to both active treatment and placebo groups.)
The effect in women receiving DHEA was, however, dramatic. Spine BMD increased by 1.7 ±0.6% (p=0.0003) during year 1 and by 3.6 ±0.7% after 2 years of supplementation in the DHEA group, whereas in the placebo group, spine BMD was unchanged during year 1 but had increased by 2.6 ± 0.9% above baseline during year 2 when they were crossed over to DHEA. This amounted to spine BMD increases of about 2% during each of the two years of DHEA supplementation for a total of nearly 4% greater spine BMD from baseline. The authors note that this 2 year change is similar to or larger than that which results from 2 years of treatment with oral estrogen, bisphosphonates (very expensive and with rare very serious side effects), or selective estrogen receptor modulators.
Moreover, the authors explain that “[s]imilar increases in spine BMD induced by pharmacotherapy are associated with a 30–50% reduction in vertebral fracture risk.”1
A new study1 reports on the effects of overeating on subcutaneous fat cells located in the upper body compared to those in the lower body. Though the study examined only subcutaneous (not visceral) fat cells in both regions, the effects of overeating differed substantially between them.
As the paper notes, fat cells can respond to extra nutrients (overfeeding) by either increasing fat-cell numbers (by creating more fat cells) or increasing the size of already existing fat cells (hypertrophy). The difference is important because newly created fat cells are small and are relatively insulin sensitive as compared to big fat cells. The results showed that on average, the size but not the number of abdominal subcutaneous adipocytes increased significantly in response to fat gain (p=0.001). The change in abdominal subcutaneous adipocyte size was related negatively to baseline size in women but not in men. That is, the women who started with smaller abdominal subcutaneous fat cells gained abdominal fat largely via adipocyte hypertrophy, whereas women with an average adipocyte size “must have” recruited new, smaller adipocytes since the average size of mature adipocytes decreased. “Virtually all men increased abdominal adipocyte size irrespective of baseline size.”1
On the other hand, femoral (leg) subcutaneous adipocyte size remained unchanged in the face of increased leg fat, where overfeeding resulted in a significant increase in lower-body adipocyte number. For both men and women, however, smaller femoral adipocytes increased the average size of mature adipocytes, whereas average adipocyte size decreased in men with femoral adipocytes larger than ~0.35 μg lipid per cell and in women with femoral adipocytes larger than ~0.75 μg lipid per cell.” In the study as a whole, ‘we confirmed that the relative fat gain in the lower body is a strong negative predictor of the change in abdominal subcutaneous adipocyte size.”1
This study helps a great deal in explaining the relative health implications of fat gain in lower body fat cells as compared to fat gain in upper body fat cells, where upper body fat cells (more likely to be larger and less insulin sensitive) are more closely linked to metabolic abnormalities such as diabetes. It also disproves the belief that the number of fat cells is relatively fixed in adulthood by showing that fat cells can not only increase in size in response to overfeeding but also their numbers can be increased.*
Additional research on the differences in signal transduction within upper body subcutaneous fat cells versus lower body subcutaneous fat cells might reveal a way of making the upper body sc fat cells function more like lower body sc fat cells, thereby reducing the health risks associated with upper body sc fat cells.
* “Using a longitudinal intervention model to study increases in body fat caused by overfeeding normal-weight adults, we found that gain of only ~1.6 kg. of lower-body fat resulted in the creation of ~2.6 billion new adipocytes within 8 wk.”
A new paper1 makes a plausible suggestion for a mechanism that may explain why it is that, if delayed too long after menopause, estrogen loses its ability to protect against cardiovascular disease and age-associated cognitive impairment.
As has been widely discussed recently, the discrepant findings on whether estrogen replacement therapy provides protective benefits to women with respect to cardiovascular risk and also risk of cognitive decline has resulted in a realization that an excessive delay in replacing estrogen/progesterone results in a loss of protective effects. In fact, in studies in which women received hormone replacement containing conjugated estrogens or conjugated estrogens and a synthetic progestagen, delayed treatment resulted in increased risk of cardiovascular disease.
The new study1 found in that in rats 9 and 15 months post-ovariectomy, estrogen replacement (17-beta estradiol) was still able to induce a significant increase in the magnitude of LTP (long term potentiation, a critical process in learning and memory) in the hippocampus, whereas in rats 19 months post-ovariectomy, the magnitude of LTP in hippocampal slices from the estrogen treated rats no longer differed from that seen in the vehicle-treated controls.
The researchers surmise that “[t]he inability of E2 [estrogen] to increase synaptic plasticity and spine density reported here and hippocampal learning reported by others after prolonged E2 deprivation might be explained by decreased hippocampal cholinergic function.” They note that “an extensive literature has documented a key role of cholinergic innervation in mediating the beneficial effects of E2 on spatial learning.” Moreover, they explain, OVX [ovariectomy] leads to a significant decrease in ChAT [choline acetyltransferase] mRNA in basal forebrain cholinergic neurons and acetylcholine release in the hippocampus beyond that of normal aging. Thus, a threshold may exist at which cholinergic function is so severely depleted that E2’s effects on synaptic function and learning cannot be elicited. In support of this idea, a recent elegant study showed that pharmacological inhibition of acetylcholinesterase in vivo rescued the ability to E2 to enhance cognitive function in aged rats 19 to 24 mon post-OVX.” It is well known that the cholinergic nervous system suffers age-related decline, one mechanism being the demonstrated reduced ability of older brains of humans to transport choline into the brain.
This is a hypothesis and has not been directly tested yet. However, there is considerable supportive evidence (as noted above). If cholinergic dysfunction is the cause of the loss of estrogenic protective effects after a “critical period” post-menopause, then a possible “fix” for this problem is to take supplemental choline (from, for example, our sugar-free choline formulation) and a cholinesterase inhibitor, such as is found in a galantamine-containing product. This might work even to restore estrogen protective effects after the “critical period” (the “use by” date) has passed.