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Biomedical subjects

Mark F McCarty

Publications and source records attributed to Mark F McCarty.

At least 55 records · Page 3Linked to original sources
PubMed2004

Sub-optimal taurine status may promote platelet hyperaggregability in vegetarians.

Although vegan diets typically have a very favorable effect on a range of vascular risk factors, several independent groups have reported that the platelets of vegetarians are more sensitive to pro-aggregatory agonists than are those of omnivores. In light of clear and convincing evidence that platelet function has an important impact on risk for thromboembolic events, it is important to clarify the basis of platelet hyperaggregability in vegetarians. A dietary deficit of long-chain omega-3 fatty acids is not likely to explain this phenomenon, since most omnivore diets do not include enough of these fats to discernibly influence platelet function. A more plausible possibility is that relatively poor taurine status--a function of the facts that plants are devoid of taurine and the human capacity for taurine synthesis is limited - is responsible. Plasma taurine levels are lower, and urinary taurine excretion is substantially lower, in vegetarians than in omnivores. Platelets are rich in taurine, which functions physiologically to dampen the calcium influx evoked by aggregating agonists--thereby down-regulating platelet aggregation. Supplemental intakes of taurine as low as 400 mg daily have been reported to markedly decrease the sensitivity of platelets to aggregating agonists ex vivo. Although the average daily intake of taurine from omnivore diets may be only about 150 mg, it is credible to speculate that a supplemental intake of this magnitude could normalize the platelet function of vegetarians in the long term; in any case, this thesis is readily testable clinically. Taurine is just one of a number of nutrients found almost solely in animal products--"carninutrients"--which are rational candidates for supplementation in vegans.

Clinical Trials as Topic↗
PubMed2004

Vascular endothelium is the organ chiefly responsible for the catabolism of plasma asymmetric dimethylarginine--an explanation for the elevation of plasma ADMA in disorders characterized by endothelial dysfunction.

Plasma levels of asymmetric dimethylarginine (ADMA), an endogenously produced competitive inhibitor of nitric oxide synthase (NOS), have been found to be elevated in a large number of disorders characterized by endothelial dysfunction; this remarkable phenomenon has yet to receive a plausible explanation. ADMA arises by proteolysis of methylated proteins throughout the body; the majority of this ADMA is catabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), found in many tissues, including those that express NOS. Since the production of ADMA can be considered constitutive, and little intact ADMA emerges in the urine, impaired catabolism is most likely responsible for elevations of plasma ADMA. The association of elevated ADMA with endotheliopathy is readily explained if we assume that vascular endothelium is the organ chiefly responsible for the catabolism of plasma ADMA--a view that is credible owing to the privileged access of endothelium to plasma, the capacity of endothelium for active transport of arginine (and methylated arginines), and the ample DDAH activity of healthy endothelial cells--and further assume that endothelial dysfunction is often attended by a loss of DDAH activity and/or an impairment of arginine transport, reducing the efficiency of ADMA catabolism. Indeed, there is recent evidence that DDAH is inhibited by endothelial oxidative stress, a typical feature of endotheliopathy; there is also some reason to suspect that arginine transport may be less efficient in dysfunctional endothelium. From this perspective, increased plasma ADMA is not the primary cause of the endothelial dysfunction in various disorders, but rather its effect--though the rise in ADMA can then exacerbate this dysfunction by inhibiting endothelial NOS. Supplemental arginine should be of some clinical benefit in disorders characterized by elevated ADMA, since it can offset that adverse impact of ADMA on NOS activity, and possibly exert other beneficial effects on endothelium--but it cannot be expected to reverse the primary cause of the endothelial dysfunction. Whether or not ADMA plays an important pathogenic role, it seems likely to emerge as a potent risk factor for adverse vascular events, since it may be viewed as a barometer of endothelial health.

Amidohydrolases↗
PubMed2004

Supplementary taurine may stabilize atheromatous plaque by antagonizing the activation of metalloproteinases by hypochlorous acid.

The rupture of atherosclerotic plaque, responsible for triggering the majority of myocardial infarctions, presumably requires proteolysis of collagen fibers and other protein components of the intercellular matrix. This is achieved by activated matrix metalloproteases (MMPs) secreted by intimal macrophages and foam cells. MMPs are synthesized as inactive pro-enzymes in which coordinate binding of the thiol group of a key cysteine residue to the active-site zinc atom blocks proteolytic activity. Physiological activation of MMPs is mediated, in large measure, by phagocyte-derived hypochlorous acid (HOCL), which can oxidize the zinc-bound thiol to sulfinic acid, thus freeing the active-site zinc. HOCL also encourages proteolysis of ground substance by inactivating proteins such as TIMP-1 that are physiological inhibitors of MMPs. In vivo, the unrestrained oxidant activity of HOCL is opposed by taurine, which reacts spontaneously with HOCL to generate taurine chloramine, much more stable than HOCL. Taurine chloramine has less impact than HOCL on MMP activation, and does not impair the activity of TIMP-1. Since tissue levels of taurine can be boosted via supplementation, taurine may thus have potential for stabilizing plaque and thereby warding off infarction--an effect that should be reinforced by taurine's platelet-stabilizing activity. In light of recent epidemiological evidence that increased expression of myeloperoxidase - the enzyme which generates HOCL--is an important risk factor for coronary disease, supplemental taurine may indeed have broader utility for suppressing both the genesis and the rupture of atherosclerotic plaque.

Arteriosclerosis↗
PubMed2004

Should we restrict chloride rather than sodium?

Low-salt diets have potential for prevention and treatment of hypertension, and may also reduce risk for stroke, left ventricular hypertrophy, osteoporosis, renal stones, asthma, cataract, gastric pathology, and possibly even senile dementia. Nonetheless, the fact that salt restriction evokes certain counter-regulatory metabolic responses-- increased production of renin and angiotensin II, as well as increased sympathetic activity--that are potentially inimical to vascular health, has suggested to some observers that salt restriction might not be of unalloyed benefit, and might in fact be contraindicated in some "salt-resistant" subjects. Current epidemiology indicates that lower-salt diets tend to reduce coronary risk quite markedly in obese subjects, whereas the impact of such diets on leaner subjects (who are less likely to be salt sensitive) is equivocal--seemingly consistent with the possibility that salt restriction can exert countervailing effects on vascular health. There is considerable evidence that sodium chloride, rather than sodium per se, is responsible for the known adverse effects of dietary salt. Other non-halide sodium salts, such as sodium citrate or bicarbonate, do not raise plasma volume, increase blood pressure, boost urinary calcium loss, or promote stroke in stroke-prone rats. Nonetheless, these compounds have been shown to blunt the impact of salt restriction on renin, angiotensin II, and sympathetic activity in humans. This may rationalize limited clinical evidence that organic sodium salts can decrease blood pressure in salt-restricted hypertensives. Furthermore, organic sodium salts have an alkalinizing metabolic impact favorable to bone health. These considerations suggest that restricting dietary salt to the extent feasible, while encouraging consumption of organic sodium salts in mineral waters, soft drinks, or other nutraceuticals--preferably in conjunction with organic potassium salts and taurine--may represent a superior strategy for controlling blood pressure, promoting vascular health, and preserving bone density. Further clinical studies should determine whether a moderately salt-restricted diet supplemented with organic sodium salts has a better and more uniform impact on hypertension than salt restriction alone, while rodent studies should examine the comparative impact of these regimens on rodents prone to vascular disease.

Causality↗
PubMed2004

Elevated sympathetic activity may promote insulin resistance syndrome by activating alpha-1 adrenergic receptors on adipocytes.

An excess of free intracellular calcium can reduce the efficiency of insulin-mediated glucose transport by blocking the dephosphorylation of GLUT-4. Classical isoforms of protein kinase C (PKC) can interfere with insulin signalling via serine phosphorylation of IRS-1 and the insulin receptor. Parathyroid hormone (PTH), by activating phospholipase C-beta in adipocytes, can promote a sustained increase in intracellular free calcium in these cells, while also activating classical PKCs. This may rationalize the fact that insulin resistance is a typical feature of hyperparathyroidism, as well as epidemiological evidence that regular ingestion of dairy products or of ethanol--which down-regulates PTH secretion--reduces risk for insulin resistance syndrome and diabetes. Alpha-1 adrenergic receptors of adipocytes--like PTH receptors--also activate phospholipase C-beta, and thus have an effect analogous to PTH on intracellular free calcium and PKC activity in adipocytes. This suggests that, via activation of alpha-1 adrenergic receptors, increased sympathetic activity in adipose tissue may promote insulin resistance syndrome. In fact, measures which provoke increased sympathetic output--such as diuretic use and severe salt restriction--are known to compromise insulin sensitivity, whereas alpha-1 antagonist drugs, as well as drugs that act centrally to suppress sympathetic activity, typically have a favorable effect on insulin function. When insulin resistance syndrome is associated with elevated sympathetic activity--for example, in hypertensives who are obese or on diuretic therapy--measures which down-regulate sympathetic activity, or, more specifically, alpha-1 adrenergic activity, may be warranted. These include centrally acting imidazoline analogs (moxonidine, rilmenidine) and alpha-1 antagonists (doxazosin, prazosin). Taurine and high-dose pyridoxine may represent practical nutritional strategies for moderating elevated sympathetic activity, and exercise training and low-insulin-response diets may be useful in this regard as well.

Adipocytes↗
PubMed2004

Marinobufagenin may mediate the impact of salty diets on left ventricular hypertrophy by disrupting the protective function of coronary microvascular endothelium.

Individuals who eat salty diets and who are "salt-sensitive" tend to have increased left ventricular mass, independent of blood pressure; this phenomenon awaits an explanation. It is clear that local up-regulation of angiotensin II (AngII) production and activity play a key role in the induction of left ventricular hypertrophy (LVH). Recent evidence suggests that a healthy coronary microvascular endothelium opposes this effect by serving as a paracrine source of nitric oxide (NO), a natural antagonist of AngII activity, and that up-regulation of this mechanism can account for the protective role of bradykinin with respect to LVH. The coronary microvasculature also possesses NAD(P)H oxidase activity that can generate superoxide, inimical to the bioactivity of endothelial NO. There is now good reason to believe that the triterpenoid marinobufagenin (MBG), a selective inhibitor of the alpha-1 isoform of the sodium pump, mediates the impact of salty diets on blood pressure;production of MBG by the adrenal cortex is boosted when salt-sensitive animals are fed salty diets. It is hypothesized that coronary microvascular endothelium expresses the alpha-1 isoform of the sodium pump, and that MBG thus can target this endothelium. If that is the case, MBG would be expected to decrease membrane potential in these cells;as a consequence, superoxide production would be up-regulated, NO synthase activity would be down-regulated, and myocardial NO bioactivity would thus be suppressed. This would offer a satisfying explanation for the impact of salt and salt-sensitivity on risk for LVH. If expression of the alpha-1 isoform of the sodium pump is a more general property of vascular endothelium, MBG may suppress NO bioactivity in other regions of the vascular tree, thereby contributing to other adverse effects elicited by salty diets: reduced arterial compliance, medial hypertrophy, impaired endothelium-dependent vasodilation, hypertensive/diabetic glomerulopathy, increased risk for stroke, and hypertension.

Angiotensin II↗
PubMed2004

Up-regulatory impact of boron on vitamin D function -- does it reflect inhibition of 24-hydroxylase?

Nutritional intakes of boron have been shown to lessen the adverse consequences of vitamin D deficiency in rodents. Pilot clinical studies suggest that this effect may be mediated, in whole or in part, by an increase in serum 25-hydroxyvitamin D. We propose that, in concentrations achievable with good diets, boron suppresses the activity of the microsomal enzyme 24-hydroxylase, chiefly responsible for catabolism of this steroid. This inhibition may reflect a direct interaction with the enzyme, or perhaps boron's ability to form a covalent complex with the product of its activity, 24,25-dihydroxyvitamin D. An up-regulatory impact of boron on 25-hydroxyvitamin D is potentially beneficial in light of the fact that the vitamin D status of many individuals is poor during winter months, and traditional supplemental doses of this vitamin are often too low to correct this problem. There is growing evidence that good vitamin D status -- as reflected by 25-hydroxyvitamin D levels -- may reduce risk for a host of prominent disorders; thus, boron may have the ability to potentiate this protection. Clinical studies also suggest that nutritional boron can up-regulate 17beta-estradiol levels in women, including postmenopausal women receiving hormone replacement therapy. The catabolism of this hormone is achieved by microsomal enzymes catalyzing vicinal hydroxylations -- a description that also applies to 24-hydroxylase. This suggests the more general hypothesis that nutritional boron can inhibit a range of microsomal enzymes which insert hydroxyl groups vicinal to existing hydroxyls in steroids -- including the enzymes which catabolize estradiol and 25-hydroxyvitamin D.

Administration, Oral↗
PubMed2004

Does bitter melon contain an activator of AMP-activated kinase?

Extracts of the unripe fruit of Momordica charantia--bitter melon, which flourishes throughout the tropics--appear to have utility in the management of type 2 diabetes. Rodent studies suggest that the thus-far-uncharacterized active components of such extracts enhance the efficiency of postprandial glucose storage in muscle and liver, and likely diminish excessive hepatic glucose output, while often down-regulating serum insulin--effects comparable to those reported for metformin. Other parallels between the actions of metformin and bitter melon in rodents appear to include: analogous effects on the hepatic activity of certain enzymes of glucose metabolism; increased expression of GLUT4 in the plasma membrane of skeletal muscle; a tendency to prevent weight gain; favorable effects on serum lipids; and an anti-promotional impact on cancer induction. Inasmuch as the clinical efficacy of metformin has recently been traced to its ability to activate AMP-activated kinase, it would be of interest to determine whether bitter melon extracts contain activators of this enzyme. The fact that bitter melon has the potential to down-regulate insulin suggests that, beyond its likely utility in the management of diabetes, it may have preventive value with respect to a wide range of disorders in which hyperinsulinemia plays a pathogenic role--and possibly could even favorably impact the aging process.

AMP-Activated Protein Kinases↗
PubMed2004

Chronic activation of AMP-activated kinase as a strategy for slowing aging.

Caloric restriction down-regulates insulin secretion and systemic IGF-I activity, and there is reason to suspect that these effects are key mediators of caloric restriction's favorable impact on longevity. Alternative strategies for down-regulating these hormones are thus of great interest; chronic activation of AMP-activated kinase (AMPK)--clinically achievable with the drug metformin--may have utility in this regard. In the liver, AMPK slows hepatic glucose output by down-regulating expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase; in skeletal muscle, it boosts the efficiency of insulin-stimulated glucose uptake by increasing expression of GLUT-4. These effects evidently mandate a down-regulation of insulin secretion. The resulting reduction of hepatic insulin activity can be expected to suppress hepatic production of IGF-I while boosting that of IGFBP-1, thereby decreasing plasma free IGF-I. AMPK can also directly stimulate IGFBP-1 synthesis in hepatocytes, and interfere with the ras/raf/erk pathway of IGF-I signaling. In non-diabetics, metformin therapy is indeed reported to reduce plasma levels of insulin and of free IGF-I; indeed, this is thought to be the mechanism whereby metformin suppresses excess androgen production in PCOS. A pro-longevity effect of the related biguanide phenformin has already been reported in tumor-prone mice, and mouse longevity studies with metformin are currently in progress. The development of AMPK activators which do not share metformin's modest risk of inducing lactic acidosis--apparently reflecting an inhibition of mitochondrial complex 1 that is not intrinsic to AMPK activity--might aid the practical applicability of this pro-longevity strategy.

AMP-Activated Protein Kinases↗
PubMed2004

AMPK activation may suppress hepatic production of C-reactive protein by stimulating nitric oxide synthase.

The utility of C-reactive protein (CRP) as an independent risk factor for vascular events may be attributable, at least in part, to a direct adverse impact of CRP on endothelial function. In particular, modestly elevated concentrations of CRP have been shown to decrease the expression of the endothelial isoform of nitric oxide synthase (eNOS) in endothelial cells; the implication of this for vascular health is evident. Strategies for decreasing elevated CRP include administration of statins, thiazolidinediones, and metformin; moderate alcohol consumption and appropriate weight loss are also helpful in this regard. Metformin's antidiabetic efficacy is now known to reflect activation of AMP-activated kinase (AMPK); AMPK can stimulate eNOS, which is expressed in hepatocytes. A recent study shows that nitric oxide suppresses the activation of Stat3 by interleukin-6 in hepatocytes; Stat3 is crucial for the IL-6-mediated induction of CRP and various other acute phase reactants. Thus, it is proposed that metformin--or AMPK---inhibits hepatic CRP production by boosting hepatic nitric oxide synthesis, which in turn impedes Stat3 activation and CRP transcription. This hypothesis should be readily testable in cultured hepatocytes. Although the impact of metformin on plasma IL-6 levels has not been reported, the possibility that AMPK activation could influence adipocyte secretion of this cytokine also merits scrutiny.

AMP-Activated Protein Kinases↗
PubMed2004

A taurine-supplemented vegan diet may blunt the contribution of neutrophil activation to acute coronary events.

Neutrophils are activated in the coronary circulation during acute coronary events (unstable angina and myocardial infarction), often prior to the onset of ischemic damage. Moreover, neutrophils infiltrate coronary plaque in these circumstances, and may contribute to the rupture or erosion of this plaque, triggering thrombosis. Activated neutrophils secrete proteolytic enzymes in latent forms which are activated by the hypochlorous acid (HOCl) generated by myeloperoxidase. These phenomena may help to explain why an elevated white cell count has been found to be an independent coronary risk factor. Low-fat vegan diets can decrease circulating leukocytes--neutrophils and monocytes--possibly owing to down-regulation of systemic IGF-I activity. Thus, a relative neutropenia may contribute to the coronary protection afforded by such diets. However, vegetarian diets are devoid of taurine - the physiological antagonist of HOCl--and tissue levels of this nutrient are relatively low in vegetarians. Taurine has anti-atherosclerotic activity in animal models, possibly reflecting a role for macrophage-derived myeloperoxidase in the atherogenic process. Taurine also has platelet-stabilizing and anti-hypertensive effects that presumably could reduce coronary risk. Thus, it is proposed that a taurine-supplemented low-fat vegan diet represents a rational strategy for diminishing the contribution of activated neutrophils to acute coronary events; moreover, such a regimen would work in a number of other complementary ways to promote cardiovascular health. Moderate alcohol consumption, the well-tolerated drug pentoxifylline, and 5-lipoxygenase inhibitors--zileuton, boswellic acids, fish oil--may also have potential in this regard.

Adjuvants, Pharmaceutic↗
PubMed2004

Targeting multiple signaling pathways as a strategy for managing prostate cancer: multifocal signal modulation therapy.

The aberrant behavior of cancer reflects upregulation of certain oncogenic signaling pathways that promote proliferation, inhibit apoptosis, and enable the cancer to spread and evoke angiogenesis. Theoretically, it should be feasible to decrease the activity of these pathways-or increase the activity of pathways that oppose them-with noncytotoxic agents. Since multiple pathways are dysfunctional in most cancers, and cancers accumulate new oncogenic mutations as they progress, the greatest and most durable therapeutic benefit will likely be achieved with combination regimens that address several targets. Thus, a multifocal signal modulation therapy (MSMT) of cancer is proposed. This concept has already been documented by researchers who have shown that certain combinations of signal modulators-of limited utility when administered individually-can achieve dramatic suppression of tumor growth in rodent xenograft models. The present essay attempts to guide development of MSMTs for prostate cancer. Androgen ablation is a signal-modulating measure already in standard use in the management of delocalized prostate cancer. The additional molecular targets considered here include the type 1 insulin-like growth factor receptor, the epidermal growth factor receptor, mammalian target of rapamycin, NF-kappaB, hypoxia-inducible factor-1alpha, hsp90, cyclooxygenase-2, protein kinase A type I, vascular endothelial growth factor, 5-lipoxygenase, 12-lipoxygenase, angiotensin II receptor type 1, bradykinin receptor type 1, c-Src, interleukin-6, ras, MDM2, bcl-2/bclxL, vitamin D receptor, estrogen receptor-beta, and PPAR-. Various nutrients and phytochemicals suspected to have potential utility in prostate cancer prevention and therapy, but whose key molecular targets are still unknown, might reasonably be incorporated into MSMTs for prostate cancer; these include lycopene, selenium, green tea polyphenols, genistein, and silibinin. MSMTs can be developed systematically by testing various combinations of signal-modulating agents, in concentrations that can feasibly be achieved and maintained clinically, on human prostate cancer cell lines; combinations that appear promising can then be tested in xenograft models and, ultimately, in the clinic. Some signal modulators can increase response to cytotoxic drugs by upregulating effectors of apoptosis. When MSMTs fail to raise the spontaneous apoptosis rate sufficiently to achieve tumor stasis or regression, incorporation of appropriate cytotoxic agents into the regimen may improve the clinical outcome.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Estrogen agonists/antagonists may down-regulate growth hormone signaling in hepatocytes--an explanation for their impact on IGF-I, IGFBP-1, and lipoprotein(a).

Estrogen agonists/antagonists, when administered orally, exert a range of effects on hepatic function, some of which are potentially protective. These effects include reduced synthesis of IGF-I and apolipoprotein(a), and increased synthesis of IGFBP-1--shifts which arguably could decrease risk for vascular disease and certain cancers. These effects are diametrically opposite to those of growth hormone (GH), which boosts hepatic production of IGF-I and apolipoprotein(a), while suppressing that of IGFBP-1. Thus, a parsimonious explanation of these phenomena is that oral estrogen blunts the efficiency of GH signaling in the liver. Oral androgenic progestins may have the reverse effect. It may be of particular value to determine whether certain estrogen agonists/antagonists can exert relatively 'hepatospecific' activity when administered orally--thus enabling down-regulation of systemic IGF-I activity and of lipoprotein(a), without however inducing a significant increase in systemic estrogen activity. Preliminary evidence suggests that flax lignans and perhaps other phytoestrogens may have potential in this regard.

Administration, Oral↗
PubMed2003

Reduction of serum C-reactive protein by statin therapy may reflect decreased isoprenylation of Rac-1, a mediator of the IL-6 signal transduction pathway.

Recent studies demonstrate that statin therapy decreases plasma levels of C-reactive protein (CRP), a potent risk factor for thrombotic vascular events. CRP is an acute phase reactant, and most circulating CRP is synthesized by hepatocytes in response to IL-6. Since statins do not appear to have a consistent impact on serum levels of IL-6, their impact on plasma CRP very likely reflects down-regulation of hepatocyte responsiveness to this cytokine. The ability of IL-6 to promote transcription of CRP is mediated, in large part, by activation of the transcription factor STAT3; this activation requires both a tyrosine phosphorylation (mediated by the IL-6 receptor complex) and a serine phosphorylation (Ser-727), the origin of which has been more obscure. There is new evidence that, when hepatocytes are exposed to IL-6, the consequent serine phosphorylation of STATS is mediated by a signal transduction pathway in which the G-protein Rac-1 plays an obligate role. Inasmuch as the proper function of Rac-1 is contingent on isoprenylation that anchors it to the plasma membrane, it is reasonable to hypothesize that statin therapy interferes with IL-6 signaling in hepatocytes by suppressing the isoprenylation of Rac-1; a decrease in the transcription of CRP would be a likely consequence of this effect. Whether or not a reduction in elevated CRP is directly beneficial to vascular health, statins can exert direct effects on vascular endothelial function that should help prevent vascular inflammation and thrombosis, and thus should be of particular benefit to subjects - such as those with high CRP levels - who are at high risk for vascular events.

C-Reactive Protein↗
PubMed2003

A low-fat, whole-food vegan diet, as well as other strategies that down-regulate IGF-I activity, may slow the human aging process.

A considerable amount of evidence is consistent with the proposition that systemic IGF-I activity acts as pacesetter in the aging process. A reduction in IGF-I activity is the common characteristic of rodents whose maximal lifespan has been increased by a wide range of genetic or dietary measures, including caloric restriction. The lifespans of breeds of dogs and strains of rats tend to be inversely proportional to their mature weight and IGF-I levels. The link between IGF-I and aging appears to be evolutionarily conserved; in worms and flies, lifespan is increased by reduction-of-function mutations in signaling intermediates homologous to those which mediate insulin/IGF-I activity in mammals. The fact that an increase in IGF-I activity plays a key role in the induction of sexual maturity, is consistent with a broader role for-IGF-I in aging regulation. If down-regulation of IGF-I activity could indeed slow aging in humans, a range of practical measures for achieving this may be at hand. These include a low-fat, whole-food, vegan diet, exercise training, soluble fiber, insulin sensitizers, appetite suppressants, and agents such as flax lignans, oral estrogen, or tamoxifen that decrease hepatic synthesis of IGF-I. Many of these measures would also be expected to decrease risk for common age-related diseases. Regimens combining several of these approaches might have a sufficient impact on IGF-I activity to achieve a useful retardation of the aging process. However, in light of the fact that IGF-I promotes endothelial production of nitric oxide and may be of especial importance to cerebrovascular health, additional measures for stroke prevention-most notably salt restriction-may be advisable when attempting to down-regulate IGF-I activity as a pro-longevity strategy.

Adaptation, Physiological↗
PubMed2003

A paradox resolved: the postprandial model of insulin resistance explains why gynoid adiposity appears to be protective.

Although an increased visceral adipose mass is clearly linked to insulin resistance syndrome and increased vascular risk, some studies suggest that the ratio of visceral to subcutaneous fat (gynoid or abdominal) is a better correlate of insulin resistance. For example, the utility of waist-to-hip ratio as a risk factor illustrates this principle--and suggests that gynoid obesity may somehow be protective. The postprandial model of insulin resistance--the hypothesis that excessive postprandial free, fatty acid (FFA) flux plays a key role in the genesis of the insulin resistance syndrome--may help to rationalize this seemingly paradoxical observation. A high proportion of this FFA flux is derived, not from adipocytes, but from meal-derived fatty acids that adipocytes fail to store following chylomicron breakdown; insulin-resistant adipocytes are notably inefficient in regard to FFA storage. Hypertrophied visceral adipocytes are poorly insulin sensitive, whereas gynoid adipocytes tend to be highly insulin sensitive. After a fatty meal, the lipoprotein lipase (LPL) activities associated with the various depots--visceral and subcutaneous adipocytes, as well as skeletal muscle--effectively compete to hydrolyze chylomicra. When circulating triglycerides are broken down by muscle or by insulin-sensitive subcutaneous adipocytes, the evolved fatty acids are apt to be stored immediately--whereas the fatty acids produced by chylomicron breakdown in the visceral depot are much more prone to escape to the circulation and contribute to high postprandial FFA flux. Thus, the LPL activity of gynoid adipocytes provides protection from the potentially adverse metabolic consequences of fatty meals--and a large mass of gynoid adipocytes presumably is a marker for high LPL activity in this depot. The ability of the postprandial model of insulin resistance to rationalize the seeming protection afforded by gynoid obesity constitutes evidence that this model has validity.

Adipose Tissue↗