The Key to Aging and Illness?

The Key to Aging and Illness?

Today, the New England Journal of Medicine published a lecture given by a scientist at MIT that goes a 

long way towards establishing a new approach to thinking about why and how we age, and how that process

is at the heart of most of the terrible afflictions that face us as we get older, namely:

dementia, heart disease, auto-immune disorders (such as arthritis), and cancer.

For most of us aging just seems to be the fault of time.  As time goes on, things wear out.  Why  would our

bodies be any different?  But the problem with that concept of aging is that bodies don't actually wear out.

The materials that make up our body are renewed constantly by the food we eat and the air we breathe.

For example, we have a new layer of skin created every three weeks.

Further, each species ages at a different rate.  If aging was just a matter of wear and tear, the bones of a dog and bear and human ought to wear out at the same rate, but they do not.  

And finally, there is the observation that all animals age in the same way.  All animals see their skin get wrinkly, their hair lose its pigment and shine, their joints get sore and inflamed, their hearts begin to fail, and cancers to appear.

A lot of research is now proving that aging is a program.  Our DNA and biology contains a program, like a piece of software, that dictates the decline in function that we call aging and its characteristic diseases.

Abundant examples now exist in animals and even humans that demonstrate if you change that program, you change the rate of aging.  And the center of control of the program we call aging is the part of the cell that creates all the cell's energy, a structures called the mitochondria.

It is now becoming clear that mitochondria set the pace and the program of aging, and changes to that program can change a person's experience of aging.  There are human populations whose mitochondria have a different approach to aging, and these populations live far longer with far less dementia, heart disease, cancer, and auto-immune disease.

Today's publication in the New England Journal reviews much of the science known about one set of genes that control this program we call aging.  The group of genes is called the sirtuins.  Dr. Gurante of MIT does a masterful job of reviewing what we know about the sirtuin genes and how they control aging.

The lecture is highly technical, so I apologize to those not so interested in such a technical paper, but even so, take a look at the section headings and marvel at the breadth of control the aging process commands:  with the right sirtuin genes animals, and likely humans, have less diabetes from obesity, less heart disease, less dementia, less cancer, and slower aging.

I share all this with you today, because I am convinced that the priorities of medical research need to shift.  Our usual approach to managing the illnesses of old age has been to have major research institutes devoted to researching each of these diseases.  These efforts should continue.  But with the emergence of knowledge about a very central control point on all these problems, the time has come for our science grants to push for a major effort to learn how to manage our aging software, and perhaps unlock a future where cancer, dementia, heart disease, arthritis are all held at bay as we enjoy a much longer and healthier life.

No research project aimed at a single disease can deliver this amazing goal, but it is increasingly likely that research aimed at our software for aging could.

To a good life,

Dr. Arthur Lavin

REVIEW ARTICLE

FRANKLIN H. EPSTEIN LECTURE

Sirtuins, Aging, and Medicine

Leonard Guarente, Ph.D.

N Engl J Med 2011; 364:2235-2244June 9, 2011

Article

Franklin H. Epstein, M.D., served the New England Journal of Medicine for more than 20 years. A keen clinician, accomplished researcher, and outstanding teacher, Dr. Epstein was Chair and Professor of Medicine at Beth Israel Deaconess Medical Center, Boston, where the Franklin H. Epstein, M.D., Memorial Lectureship in Mechanisms of Disease has been established in his memory.

Populations in developed countries continue to grow older, as medical advances allow baby boomers to march inexorably onward. Many of the most important diseases that lead to disability and death occur late in life, indicating that aging itself is a key risk factor. Recent research into the science of aging has identified genes and pathways that appear to control the aging process. This review describes one such family of antiaging genes, the sirtuins, and details progress in understanding the biology that undergirds their promise as therapeutic targets.

In the past century, medical research has led to the development of new therapeutic agents, including antibiotics and antiviral and anticancer drugs, as well as surgical interventions, such as coronary-artery bypass grafting, among others. Since many important diseases often occur later in life (e.g., diabetes, neurodegenerative diseases, cancer, cardiovascular disease, proinflammatory diseases, and osteoporosis), aging is an important risk factor for these conditions. During the past decade, research on aging, which began in simple laboratory organisms, has identified important genes and pathways that contribute to longevity. Included among these is the family of nicotinamide adenine dinucleotide (NAD)–dependent protein deacetylases termed sirtuins.1,2 These proteins can extend the life span in model organisms and are important in mediating the salutary antiaging effects of a low-calorie diet (calorie restriction). Mammals have seven sirtuin homologues, which perform nonredundant functions in adapting human physiology to environmental stressors, such as food scarcity. Small molecules have been identified that reportedly inhibit as well as activate sirtuins in vivo and in vitro. Whether such molecules could have antiaging properties is an interesting but open question.

Sir2 is one of a complex of proteins that mediate transcriptional silencing at selected regions of the yeast genome. Mutations that extend the replicative life span of yeast mother cells have been shown to increase the silencing activity of Sir2 at the ribosomal DNA repeats.3-5 Although the silencing of ribosomal DNA has turned out to be an idiosyncratic feature of aging in yeast, the role of Sir2-related gene products (sirtuins) in aging appears to be universal. Sir2 orthologues slow aging in the nematode Caenorhabditis elegans, in the fruit fly Drosophila melanogaster, and in mice.6-8 The sirtuins have been shown to have NAD-dependent protein deacetylase activity, which is associated with the splitting of NAD during each deacetylation cycle (Figure 1FIGURE 1Enzymatic Activity of Sirtuins.).9 Of the mammalian sirtuins, SIRT1, 2, 3, 4, 5, and 6 have been shown to have this activity.10Some SIRT family members (e.g., SIRT4 and SIRT6) also have ADP-ribosyltransferase activity.1,2,10

In mammals, the Sir2 orthologue SIRT1 is primarily a nuclear protein in most cell types and has evolved to deacetylate transcription factors and cofactors that govern many central metabolic pathways (Figure 2FIGURE 2Categories of SIRT1 Targets for Deacetylation and Their Associated Diseases.). Targets of SIRT1 include transcriptional proteins that are important in energy metabolism, such as nuclear receptors, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), and forkhead box subgroup O (FOXO).11-14 SIRT1 also regulates components of the circadian clock, such as BMAL1 and PER2, which underscores the interconnectedness of protein acetylation, metabolism, circadian rhythm, and aging.15,16 SIRT1 is also closely coupled to AMP-kinase activity in a mutually enforcing mechanism that adjusts cellular physiology for conditions of energy limitation.17

Other categories of SIRT1 targets relate to stress tolerance (p53, hypoxia-inducible factor 1α and 2α, and heat-shock factor protein 1),18 DNA repair (NBS1, PARP1, Ku70, and WRN),18 and inflammation (nuclear factor κB).19 All told, the breadth of SIRT1 substrates indicates that its activity is poised to regulate metabolism and stress response.

One early indication that SIRT1 might be important in diseases of metabolism was the finding that the protein could influence differentiation and fat accumulation in the 3T3-L1 adipose-cell line and in primary preadipocytes in rats.20 In a second case, calorie restriction triggered a SIRT1–PGC-1α–dependent increase in muscle mitochondrial biogenesis21 and the activation of fatty acid oxidation by SIRT1 and peroxisome-proliferator–activated receptor α (PPAR-α),22 which together favor insulin sensitivity and evidently a slower rate of aging-related decline. In liver, SIRT1 has been found to govern two pathways with opposing effects on gluconeogenesis. On the one hand, the activation of PGC-1α and FOXO1 appears to favor glucose production,12 whereas the deacetylation and destabilization of the cyclic AMP response-element–binding (CREB) coactivator CRCT2 would suppress it.23 The relative importance of each pathway may switch as a function of the duration of fasting to fine-tune the magnitude of glucose production over time. In steady-state calorie reduction, the net effect of these pathways results in a mild elevation in glucose production.

The oral administration of the putative SIRT1-activating compounds has been shown to mitigate the prodiabetic effects of a high-fat diet without major toxic effects, which suggests that activation of SIRT1 is antidiabetic and not pharmacologically detrimental. This hypothesis was first shown with the natural product resveratrol24,25 and was subsequently corroborated with more selective synthetic-activating compounds.26 In the latter case, efficacy was also shown in a genetic model of murine obesity (the leptin-deficient ob/ob mouse) and in obese rats. Although these antidiabetic outcomes are consistent with known effects of SIRT1 on muscle, fat cells, and liver, recent studies have shown that this sirtuin also functions in the hypothalamus to control feeding behavior and energy expenditure.27,28

It has been argued that the SIRT1-activating compounds that have been described to date do not directly activate this sirtuin,29,30 a topic that is discussed in a later section. However, it is striking that several different genetic models of SIRT1 overexpression in transgenic mice also prevent diabetes. In one model, leanness and increased insulin sensitivity were shown to occur under standard laboratory conditions.31 In two other models, there was protection against metabolic decline induced by a high-fat diet or, more strikingly, by normal aging.32,33 In addition, SIRT1 activation, whether chemical or genetic, has been associated with changes in genomic transcriptional patterns normally induced by calorie restriction.34,35 All told, these genetic studies provide strong evidence that SIRT1 plays a central role in driving the phenotype of rodents toward metabolic fitness. Therefore, among the possibilities it seems most likely that the SIRT1-activating compounds work by the activation of SIRT1 in vivo (either directly or indirectly).

Studies of SIRT1 transgenic mice also suggest that activation may be protective against other diseases of aging (e.g., bone loss and an inflammation-induced model of liver cancer).8 The antiinflammatory effect of sirtuins may be much broader, since both SIRT1 and SIRT6 repress the activity of the major proinflammatory transcription factor, nuclear factor κB.19,36 In other murine studies, it was found that SIRT1 may be protective against colon cancer37 and breast cancer.38 The fact that SIRT1 represses hypoxia-inducible factor 1α furthers its candidacy as a tumor suppressor. However, the relationship between SIRT1 and cancer may not be totally straightforward, since other studies suggest that this sirtuin may also have oncogenic properties in certain contexts.39,40 The mitochondrial sirtuin SIRT3 (which is discussed below) has recently emerged as another interesting target for cancer therapy.

SIRT1 appears to possess cardiovascular protective properties beyond those deriving solely from metabolic fitness. For example, sirtuins may protect against hypertrophy in cardiac and smooth-muscle cells. Transgenic mice that overexpress SIRT1 in the heart are protected against pathological cardiac hypertrophy (Figure 3FIGURE 3Four Mechanisms of SIRT1 Protection against Cardiovascular Disease.).41 SIRT1 also protects smooth muscle by inhibiting the expression of the angiotensin receptor AT1.42,43 AT1^−/− mice produce lower levels of reactive oxygen species and live longer than normal mice.44 Further illustrating the functional interplay between SIRT1 and SIRT3, the reduction in reactive oxygen species in AT1^−/− mice appears to be mediated by elevated levels of SIRT3.

The earliest connection between SIRT1 and endothelial cells was the finding that SIRT1 deacetylates and activates endothelial nitric oxide synthase (eNOS).21 The activation of eNOS and repression of AT1 suggest that SIRT1 activity ought to curb high blood pressure. SIRT1 also inhibits the senescence of endothelial cells,45 and its salutary effect on these cells may mitigate atherosclerosis. Interestingly, calorie restriction is known to protect against atherosclerosis,46 and many of the physiological effects of calorie restriction are blunted in eNOS^−/−mice.21 These findings all indicate that SIRT1 helps facilitate the favorable effect of calorie restriction on cardiovascular function by its effects on eNOS, AT1, and perhaps other targets.

Another function of SIRT1 that may be critical in cardiovascular disease is its regulation of fat and cholesterol homeostasis. In addition to triggering β-oxidation of fatty acids in calorie restriction,22 SIRT1 also exerts two opposing effects on fat and cholesterol synthesis. SIRT1 deacetylates and activates the nuclear receptor liver X receptor (LXR), which up-regulates the ATP-binding cassette transporter A1 to facilitate reverse cholesterol transport from peripheral tissues.11 Likewise, SIRT1 was also shown to deacetylate and activate the nuclear bile acid receptor farnesoid X receptor (FXR) to increase its dimerization with its partner retinoid X receptor and its activity.47 Thus, LXR and FXR activation by SIRT1 has the potential to increase the production of high-density lipoprotein (HDL) cholesterol and protection against atherosclerosis by facilitating cholesterol removal.

But LXR also activates the gene encoding the sterol regulatory element-binding protein 1 (SREBP1) in liver to drive fat and cholesterol synthesis. Remarkably, LXR activation by SIRT1 in liver may be counteracted by an opposing SIRT1 activity, deacetylation of SREBP1 and repression of its activity.48,49 The subtlety in control of fat synthesis is reminiscent of the control of glucose synthesis discussed above; SIRT1^−/− mice were found to be prone to liver steatosis in some studies22,50,51 and protected in another,52 possibly because of differences in the experimental protocols.

Finally, the demonstrated protective effect of SIRT1 in the kidney would also be cardioprotective by aiding the control of blood pressure. In this organ, SIRT1 protects tubular epithelium53 and medullary cells54 and mediates kidney-protective effects of calorie restriction.55 Although not all of the effects of sirtuin on cardiovascular health are known, this is an area with much research potential.

As humans are living longer, neurodegenerative diseases have become a sobering obstacle to healthy aging. It is estimated that Alzheimer's disease alone will affect up to one third of those lucky enough to win the longevity lottery.56 Although methods to detect early stages of Alzheimer's disease have become ever more sensitive, treatment approaches remain elusive. Neuronal stress (e.g., in cultured neurons57 or in cyclin-dependent kinase 5 transgenic mice58) was mitigated by the overexpression of SIRT1, prompting the question as to whether this sirtuin might restrain Alzheimer's disease.

Indeed, SIRT1 overexpression in the brain has been shown to reduce the load of β-amyloid peptide, the toxic agent that is generated by proteolytic cleavage of amyloid precursor protein in mice that overexpress two human genes that predispose to early Alzheimer's disease (Figure 4FIGURE 4Two Mechanisms of SIRT1 Protection against Alzheimer's Disease.).59 By activating the gene encoding α-secretase, SIRT1 directed the processing of amyloid precursor protein along a pathway that avoided the production of β-amyloid peptide and thus protected against the disease. SIRT1 activated the α-secretase gene by deacetylating its transcriptional activator, the retinoic acid receptor β.

β-Amyloid peptide gives rise to a protein aggregate of plaques in the brain of patients with Alzheimer's disease. In mice overexpressing β-amyloid peptide, the level of plaques was reduced in mice that also overexpress SIRT1. Another hallmark of Alzheimer's disease in humans is an increase in the number of aggregates or tangles of the tau protein in neurons. Indeed, β-amyloid peptide and tau have been two leading candidates for the causal agent of Alzheimer's disease.56 In a separate study in mice,60 SIRT1 was shown to deacetylate tau protein to destabilize it and reduce tangles (Figure 4).

Beyond frank diseases, cognitive decline is another malady of aging. Recent studies suggested that SIRT1 also benefits learning and memory in mice61,62 by activating the gene for brain-derived neurotrophic factor (BDNF). SIRT1 appears to potentiate activity of the BDNF transcription factor CREB and may generally promote activation of CREB target genes in the brain. Important questions remain with regard to the potential of sirtuins as therapeutic targets in the brain. Can SIRT1 affect other neurodegenerative diseases? Might other sirtuins (SIRT2, 3, 4, 5, 6, and 7) play a role in combating brain diseases of aging? Finally, will sirtuin drugs that are being developed to protect against diabetes cross the blood–brain barrier and, if not, can such drugs be developed?

Studies of the mitochondrial sirtuins (SIRT3, 4, and 5) have suggested that sirtuins mediate physiologic adaptation to reduced energy consumption. All three of these sirtuins modify mitochondrial proteins governing metabolic pathways that are important in energy deprivation (Figure 5FIGURE 5Three Mitochondrial Matrix Sirtuins.). SIRT4 was shown to repress the enzyme glutamate dehydrogenase (by ADP-ribosylation), which determines the utilization of amino acids as energy sources.63 In beta cells or liver, SIRT4 activity declined during calorie restriction, which allowed glutamine to feed directly into catabolic metabolism. Thus, in SIRT4^−/− mice or in wild-type calorie-restricted mice, glutamine is a fuel source for glucose synthesis in liver and also drives insulin secretion by beta cells. Remarkably, SIRT4 depletion was also recently shown to increase fatty acid oxidation.64 SIRT5 was shown to deacetylate and activate carbamoyl-phosphate synthase 1, the first and limiting enzyme in the urea cycle.65,66 The demonstrated increase in SIRT5 activity during calorie restriction activates the urea cycle to facilitate the disposal of ammonia when amino acids are used as fuel sources.

SIRT3 was shown to deacetylate long-chain acyl dehydrogenase and other enzymes that are involved in β-oxidation of fatty acids, as well as the urea cycle.67,68 A recent study in C. elegans also revealed the close linkage of the sirtuin SIR-2.1, fatty acid oxidation, and longevity.69 It has been speculated that the production of ATP from catabolism of fat rather than carbohydrates may itself be protective against reactive oxygen species and aging.70

New findings more directly link SIRT3 and the production of reactive oxygen species. SIRT3^−/− cells produce increased levels of reactive oxygen species and have a concomitant reduction in ATP production.71,72 This finding suggests that SIRT3 may deacetylate components of the electron transport chain to render oxidative phosphorylation more efficient and less affected by reactive oxygen species. Indeed, SIRT3^−/− mitochondria show increased acetylation of electron transport chain (ETC) components and reduced activity of ETC complexes I and III in isolated mitochondria.71,73 Moreover, SIRT3 was also recently shown to deacetylate and activate mitochondrial superoxide dismutase 2 (SOD2)74,75 and isocitrate dehydrogenase 2 (Idh2),76the latter of which generates NADPH for the glutathione pathway of detoxification of reactive oxygen species in mice.

An example of the potential link between SIRT3 and aging was shown in a murine model of hearing loss.76 By 12 months of age, wild-type mice showed complete hearing loss, which is triggered by oxidative damage in the spiral ganglia neurons and sensory hair cells in the cochlea. Hearing loss and oxidative damage were completely prevented by calorie restriction in these mice. However, SIRT3^−/− mice were resistant to the protective effects of calorie restriction against hearing loss and oxidative damage. If this effect of SIRT3 extends to other neuronal types or more broadly to non-neuronal tissues, SIRT3 activators may be the simplest and most direct way to counteract aging itself by triggering mechanisms resembling those of calorie restriction. For example, SIRT3 was shown to protect cardiovascular function by suppressing the production of reactive oxygen species in endothelial and cardiac cells.77

Finally, the ability of SIRT3 to suppress reactive oxygen species suggests that it may be involved in tumor suppression. Indeed, SIRT3^−/− mice generate more reactive oxygen species and are more susceptible to mammary tumors than normal mice.72Recently, SIRT3 has been linked to the metabolic reprogramming in cancer cells termed the Warburg effect, which enforces the glycolytic production of ATP. The reactive oxygen species that are produced when SIRT3 activity is suppressed activate nuclear hypoxia-inducible factor 1α,78,79 which turns on genes for glycolysis and angiogenesis. Indeed, enforced SIRT3 expression reversed the Warburg effect in many tumor-cell lines.79 Moreover, a large percentage of human tumors (up to 40% of breast and ovarian cancers) show inactivation of SIRT3.72,79 It will be critical to further validate the possibility that the loss of SIRT3 is a major determinant of the Warburg effect and cancer.

This section will focus on small-molecule activators of SIRT1 rather than inhibitors, which have also been described.80 The first studies of chemical activators of sirtuins focused on SIRT1. The polyphenols, such as resveratrol, were identified by screening compounds for boosting the deacetylation of synthetic peptidyl substrates labeled with a chemical fluorophore group.81Subsequently, chemically distinct classes of SIRT1 activators that had higher potency than polyphenols were identified with the use of a different assay with fluorophore-containing peptides.26 Both polyphenols and newer activating compounds were shown to increase the binding affinity of SIRT1 for the peptide substrates used.

Questions were first raised regarding the mechanism of activation by resveratrol since there was a lack of activation with the use of nonfluorophore-containing peptides.29 It was subsequently reported that the nonpolyphenolic compounds also did not activate SIRT1 on peptide substrates lacking the fluorophore.30 These findings led to the proposal that the activating compounds interacted with the fluorophore and that their effects in vitro and in vivo were not mediated by SIRT1. A second school of thought proposed that activators such as resveratrol might target other proteins in cells (e.g., AMP kinase82) to affect SIRT1 indirectly. Relevant to this idea, resveratrol has been shown to inhibit mitochondrial ATP synthase,83,84 although such an effect may not occur at moderate yet efficacious concentrations. Finally, a more recent study responded to these challenges by showing that several classes of the nonpolyphenolic compounds can activate SIRT1 with the use of peptide substrates lacking any chemical modifications.85 This latter study reported a mechanism that was based on allosteric modulation of SIRT1 by the drug, which was dependent on the amino acid sequence of the protein substrate.

How can these seemingly disparate findings be reconciled? The model in which the compounds do not affect SIRT1 at all seems unlikely, given the congruence of their in vivo effects and genetic activation of SIRT1. It is also inconsistent with examples in which the effects of activators in cells or mice are SIRT1-dependent.86 To me, the most likely possibility seems to be that the compounds do bind directly to SIRT1 as described or to a component of a SIRT1 complex in cells. The activation mechanism in vivo could involve an increase in the binding affinity for protein substrates by the allosteric mechanism mentioned above. Alternatively, the activation mechanism could relate to other proteins in cells that bind to and modulate SIRT1 activity. One interesting example is the protein called deleted in breast cancer 1 (DBC1), which is a natural inhibitor of SIRT1 activity in many cell types.87,88 Pharmacologic activation may involve the binding of compounds to SIRT1 to release active enzyme from the SIRT1–DBC1 complex. Consistent with this idea, knocking out DBC1 increases deacetylation of SIRT1 targets in cells and elicits a phenotype resembling SIRT1 transgenic mice.50 In any case, the intense focus on SIRT1-activating compounds should clarify mechanisms of action conclusively.

Sirtuins were originally identified as antiaging proteins in model genetic organisms and have emerged as mediators of the beneficial effects of calorie restriction in mammals. The mammalian Sir2 orthologue, SIRT1, is an NAD-dependent deacetylase that is involved in many central pathways governing physiology and stress management. Genetic or pharmacologic activation of SIRT1 can benefit numerous diseases in murine models. Indeed, two different SIRT1-activating compounds are now in a diverse set of phase 1 or phase 2 human trials (ClinicalTrials.gov numbers, NCT00937326, NCT00964340, NCT01014117, NCT01018017, NCT01018628, NCT01262911, NCT01031108, and NCT01154101). Beyond SIRT1, there are six other mammalian sirtuins (SIRT2, 3, 4, 5, 6, and 7), and all may turn out to have therapeutic potential with the use of activators or inhibitors. Among these sirtuins, SIRT3 is extremely interesting, because it appears to suppress one of the contributing causes of aging itself, reactive oxygen species in mitochondria. Indeed, genetic polymorphisms in the SIRT3 promoter have been associated with extreme longevity in an Italian population,89,90 although these studies will have to be replicated in other groups. In conclusion, sirtuins are a unique class of proteins that link protein acetylation to metabolism and exert profound effects on mammalian physiology and diseases of aging. The development of drugs that target sirtuins to treat these diseases is ongoing.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

From the Paul F. Glenn Lab and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA.

Address reprint requests to Dr. Guarente at the Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Ave., #68-280, Cambridge, MA 02139, or at leng@mit.edu.

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*Disclaimer* The comments contained in this electronic source of information do not constitute and are not designed to imply that they constitute any form of individual medical advice. The information provided is purely for informational purposes only and not relevant to any person's particular medical condition or situation. If you have any medical concerns about yourself or your family please contact your physician immediately. In order to provide our patients the best uninfluenced information that science has to offer,we do not accept samples of drugs, advertising tchotchkes, money, food, or any item from outside vendors.

Dear Family,

 

Advanced Pediatrics offers a distinctive approach to medical care --- putting outcomes first. With that in mind, we work towards being a source of unbiased information, promoting close working relationships with families, and being as responsive as possible. As a family in the practice, you are quite familiar with our approach. In fact, you likely think it is the norm for pediatric practices. I can assure you, it is not.

 

This week the Archives of Internal Medicine, a leading publication of the AMA, published an article based on a national report on how best to practice medicine. A nationally recognized family practitioner at Brown University created three teams of five doctors each from around the country. The teams were pediatricians, internists, and family practitioners. I was honored to be chair of the pediatric group. 

http://archinte.ama-assn.org/cgi/content/short/archinternmed.2011.231v1

 

Each team was charged with identifying 5 recommendations, each of which would ask practicing doctors to stop doing something that helps no one and creates unnecessary costs. The team I led included pediatricians from Philadelphia to California and we worked with a research assistant to do careful literature reviews that could support our recommendations. Our recommendations were field tested with two national groups of practicing pediatricians who also embraced our proposed changes in practice.

 

Overall, the recommendations are an attempt to place practices on the firm basis of doing only what works and is necessary.

 

The outcome of our work led to these 5 recommendations being made to the nation's pediatricians:

1. Do not prescribe antibiotics for a sore throat unless the patient tests positive for strep throat.
2. Do not obtain X-ray or CT scans of the head for minor head injuries without loss of consciousness or other risk factors.
3. Do not refer children with ear infections to ENT specialists early in the course of recurrences.
4. Advise families not to use cough and cold medications for their children.
5. Use inhaled steroids to manage asthma appropriately.

Advanced Pediatrics is pleased to have reached similar conclusions many years ago. Families in the practice should find the specific recommendations and the overall approach very familiar.

 

The publication of this article created a broad response in the country's media, including items run on PBS, NPR, the Wall Street Journal, Time, US News & World Report.

 

This project is a powerful instance of validation for our way of thinking and caring for families at Advanced Pediatrics. The process has led to a national organization of physicians, a working group of pediatricians, a designated medical researcher, and dozens of practicing pediatricians around the country endorsing our approach to the care of children.

 

Hopefully this report confirms that your choice of medical care for your children has been well-placed.

 

Thanks again for your trust, we look forward to continuing to find ways to improve the community's health.

Dr. Arthur Lavin

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*Disclaimer* The comments contained in this electronic source of information do not constitute and are not designed to imply that they constitute any form of individual medical advice. The information provided is purely for informational purposes only and not relevant to any person's particular medical condition or situation. If you have any medical concerns about yourself or your family please contact your physician immediately. In order to provide our patients the best uninfluenced information that science has to offer,we do not accept samples of drugs, advertising tchotchkes, money, food, or any item from outside vendors.

Anesthesia and Childhood: Time for Caution

Image via WikipediaAnesthesia and Childhood:  

Time for Caution

Anesthesia is one of the great gifts of modern medicine.  It has given us important medical interventions that would otherwise be too painful to bear.

The power of effective anesthesia to eliminate pain has opened up the door to many interventions, and has led to a veritable explosion of procedures in the developed world.  Of course, not all of these procedures are truly necessary, so when we find out that anesthesia has its dangers, it is prudent to take note.

In April, 2011, the world's leading medical journal, The New England Journal of Medicine, published an essay from the FDA outlining some disturbing  concerns about the effect of anesthesia on a child's mind.

http://www.nejm.org/doi/pdf/10.1056/NEJMp1102155

The main worry is that a brain exposed to anesthesia in childhood is more likely to develop learning disabilities.  A key point to be made is that this possible adverse impact is, at this time, a cause for concern, but not a proven cause.  Animal studies do prove that with enough exposure to anesthetics, there is a clear connection to increased risk of impaired cognition.  In humans, the two studies cited show an association, not a proven cause, connection between anesthesia prior to age 3 and later learning disorders.

I present this essay to you now, not to say that children under age 3 should not have anesthesia if they need it.

But, given this concern, it does seem very prudent not to proceed with a procedure that is anything less than necessary.

Dr. Arthur Lavin

---

*Disclaimer* The comments contained in this electronic source of information do not constitute and are not designed to imply that they constitute any form of individual medical advice. The information provided is purely for informational purposes only and not relevant to any person's particular medical condition or situation. If you have any medical concerns about yourself or your family please contact your physician immediately. In order to provide our patients the best uninfluenced information that science has to offer,we do not accept samples of drugs, advertising tchotchkes, money, food, or any item from outside vendors.

Sugar: Perhaps More Bitter than Sweet

Sugar:  Perhaps More Bitter than Sweet

We seem to live in an era in which everything we eat takes its turn being suspect, only to find a few weeks later that it is not so bad after all.

So when articles appear that suggest plain old sugar can cause real harm, it makes sense to be very skeptical.  

On April 13, 2011, the New York Times Magazine published a very serious review of the evidence for how sugar may indeed be harmful.

The entire article appears at the end of this essay, I encourage you to read it to form your own conclusions.

Here are some of my impressions.

Definitions of Sugars
 

First, some definitions, in particular, what is sugar?

Sugar is easy to understand, it is the sweet stuff in what we eat.

But to follow the discussion, we do need to know a little of its chemistry.

All sugars are made up of three types of atoms, carbon, hydrogen, and oxygen.  If you take a string of carbon atoms and attach a number of water molecules to them, you have a sugar.  The main chemistry lesson to learn about sugar, however, is that it is key fuel for life.

Chemical names for most sugars end in the letters "ose".  Notice  that all the familiar types of sugar all do end on "ose:"  glucose, fructose, lactose.

Glucose is a sugar molecule with 6 carbons in it.  Like most biologically active molecules, glucose come in right and left handed versions.  The right-handed version of glucose is called dextrose.  Fructose is a sugar molecule with 5 carbon atoms in it.  If you link glucose and fructose together, you get sucrose.  Then there is a sugar only found in the breast milk of mammals, lactose.

Sugar molecules are some of life's main sources of energy.  Only fat provides more energy per ounce than sugar.  But sugar is the essential fuel of the human brain.

Glucose turns out to be the key sugar of life.  This is the sugar made by plants via photosynthesis.  And glucose is the fuel that the human brain actually needs to work.

Glucose can be chemically combined to other sugars easily, and in several ways. Two  are of great importance to mention now.  If you make a very, very long string of glucose molecules bound to each other, you create starch.  But if you just bond one glucose molecule to one fructose molecule, you get sucrose.

Sucrose is the main commercial sugar of history.  It is made by some plants, such as pineapple, apricot, sugar beets, and sugar cane.  It is the sugar in all sugar packets, bowls of sugar, and sacks of sugar.

Fructose is the sugar plants make to provide for their seeds in fruit.  Most seed-bearing parts of plants have fructose in them, such as apples, tomatoes, corn.

Starch is another type of sugar that plants use to help their seeds have food to use.  Foods rich in starch include bananas, potatoes, and wheat.  Although starch is not sweet, it is simply a very long chain of glucose.  If you eat any starch, it is quickly turned into glucose soon after you start chewing it.

The Health Consequences of Sugar 

Be sure to read the NY Times article fully below to get the whole story, but again, my impressions are that there really is very big problem in eating too much fructose.

It turns out that there is a very big difference in the way that the human body uses glucose and fructose.  Glucose is the preferred fuel of the human body, of every cell, and is required by the brain.  As such, when a molecule of glucose shows up, any cell in the body can use it directly, without any change in the glucose molecule.

Fructose, in stark contrast, needs to be changed in the liver into a saturated fat, palmitate in order to be burned.   This is true for all forms of fructose, including the sugar in most fruits and vegetables, the fructose in high fructose corn syrup, and table sugar or sucrose.

A key fact is that the dangers of fructose are totally dependent on the amount that you eat, no matter if the fructose is eaten by fruit, high fructose corn syrup, or table sugar.  A little bit is truly harmless.  More than some number of pounds a year begins to cause harm.

No one knows how many pounds a year of fructose containing sugar starts to be toxic, but we know that when Americans ate about 40 pounds of it a year there was little evidence for harm.  We are now at about 90 pounds a year, and the evidence for harm is striking.

How do you know if you are eating too much fructose?  It turns out that if your only source of sugar is natural fruit and vegetable, then it is very hard to get too much.  Once you start eating sugar in processed foods, the situation changes.  To add about 40 pounds a year of extra sugar, all you need to do is add about 200 calories a day to your diet from sugar, that equals about a can and half of regular Coca-Cola or 2 cups of apple juice, that's it.  Now that amount is fairly safe.  Once you hit about 1 1/2 to twice that amount, then the bad things begin to happen.

What sort of problems does excessive fructose appear to cause?

Heart disease, high blood pressure both via diabetes, and  common cancers.

And, perhaps most surprisingly, the main way fructose causes such most serious trouble is via an essential hormone- insulin.

Insulin is a hormone familiar to many of us.  It's main purpose is to help the body manage the fuel it needs to run its operations.  Insulin is absolutely necessary to help glucose get inside many cells that use it.  It also turns out to be a hormone that helps the body's cells decide on whether to grow or remain dormant.

Most people know that diabetes is related to insulin.  It turns out that diabetes is essentially a problem caused by insulin failing to work, leading to .  It can fail to work either by not being made, or being made and finding its target cells no longer respond to it.  Either way, glucose cannot be used properly and accumulates in the blood, raising glucose levels in the body.

If insulin is working properly, then if you eat a meal, insulin will be created to help the glucose eaten to enter the cells that need it for immediate use to burn or for later use to store.

The important point here is that when you eat, insulin levels normally go up.

It is this fact that leads to the serious impact of fructose on health, if eaten to excess.   The two main health hazards from excessive fructose are heart disease and cancer.

Heart Disease and Hypertension via Diabetes

As noted above, the danger of fructose has everything to do with how much you eat over time.  People who eat less than 40 pounds of sugar a year, or any amount of sugar in fruits and vegetables, are fine.

Once you get to about 70 pounds a year, trouble begins.  The average sugar intake in America is about 90 pounds a year, and rising.

What happens when you eat too much sugar (specifically fructose)?

The fructose can only be used as fuel if it is turned into a saturated fat, palmitate.  So if you eat enough fructose, the liver, which does the conversion, can start to accumulate this fat.  As the fat accumulates, it has a biochemical impact on the liver, as well as the rest of the body.

Five things happen if enough of the fat from sugar accumulates:

• Your level of fat in the blood (triglycerides) can go over the safe level of 150.
• Your level of the "good" cholesterol, HDL, can go down below the safe level of 40 (males) or 50 (females).
• You can become obese with waist size exceeding the safe level of 40 inches in men or 36 inches in females
• Your blood pressure can go above the safe level of 130/85.
• Your fasting glucose level starts to rise and may exceed the safe level of 110.

If you develop 3 of these 5 problems, you have what is called the metabolic syndrome.  

The metabolic syndrome is becoming very, very common.  About 75 million Americans actually have this problem right now, and the numbers are climbing rapidly.  Even at 75 million, that means 25% of America has a problem that causes most heart attacks.

Notice that the metabolic syndrome can cause obesity, hypertension, heart disease, and with the rise in the fasting glucose level, diabetes.

The accumulation of fat in the system directly blunts the ability of insulin to do its job, that leads to diabetes and the other alterations noted above.

It appears that the #1 cause of metabolic syndrome is simply eating too much fructose!  

If the research reviewed in the NY Times article below is substantiated, it will turn out that a rather large amount of high blood pressure, diabetes, and heart attacks will be due to excessive sugar intake (over 200 calories a day from sugar would do it).

Cancer

We tend to think of insulin as mainly having to do with sugar levels in the blood and diabetes.  But a growing body of information points to the role of insulin in cell growth.

We know that before birth, the developing fetus has the rate of its growth determined in large part by levels of insulin that are circulating.

Babies whose Mom's have elevated blood sugar levels, and thereby produce extra insulin during pregnancy, are much larger at birth than expected.

Recently, scientists have found that insulin plays a central role in helping cells decide whether to divide or stay dormant.  It also plays an important role in how determining how much glucose a tumor cell can get to grow.

Either way, it is becoming increasingly clear that increased insulin levels can increase the risk of cancer.  Cancers that seem particularly sensitive to insulin include breast and colon cancer.  One group of scientists have estimated that as much as 80% of all cancers in the US can trace some of their roots to insulin.  Compare that to the dramatic impact of tobacco on cancer, which is responsible for 33% of all cancer.

Because of the way in which fructose is digested and used, it can cause insulin levels to rise and stay elevated.  It is in this way that an emerging possibility that sugar may be a major cause of cancer is growing.

Bottom Lines:

The Basics

1. Be sure to read the NY Times article at the end of this post it has a detailed discussion of the above summary points.
2. Not all sugars are the same.   Glucose and lactose appear to be safer to eat than fructose.
3. Fructose comes in three main forms:

• The sugar found in most fruits and vegetables.  Eating fructose in this way appears to be very safe.
• Sucrose- the sugar found in sugar bowls, many processed foods.
• High-fructose corn syrup- another major sweetener in many processed foods.  (Processed foods are any foods that require a factory or bakery to create)

The Problems

1. If you eat less than 40 pounds of fructose sugars a year (about 200 calories a day, or 12 ounces of soda), you should be fine.
2. Trouble begins at 70 pounds of fructose sugars a year and up.  Americans are at about 90 pounds a year on average today.
3. Once you start eating too much fructose-sugar a day, your metabolism changes.  Fats and sugars are handled differently by your body.  Insulin levels rise, good cholesterol levels fall, blood pressure rises.
4. When enough of these changes occur, you have the metabolic syndrome (see above for details).  About 1 in 4 Americans have this syndrome now.  You do not have to be overweight to have the metabolic syndrome.
5. If eating sugar has caused the metabolic syndrome, your risk of heart disease, high blood pressure, and cancer, is sharply increased.
6. If one decreases how much sugar you eat, to below 40 pounds a year, the metabolic syndrome can go away and with the increased risk of heart disease, high blood pressure, and cancer.

Table sugar, sugar in foods, high-fructose corn syrup, all turn out to be unhealthy to eat.   The evidence is strong enough that parents should pay attention to what their families eat.

Specifically:

1. Do not buy or serve fruit juices of any kind.
2. Do not buy or serve candy except for special occasions.
3. Do not but or serve cereals or other foods that have sugar of any sort added.
4. Avoid eating anything that has sugar or high-fructose corn syrup added to it.
5. Starch, which contains no fructose, is not as potentially harmful as sugar.

It is sad to see sugar turn out to be potentially harmful.   But the evidence has become compelling.  Certainly there is still room for enjoying a bit of sugar now and then, but to keep under the 40 pound a year target, we will all have to eat much less sugar than we do now.

To your health,

Dr. Arthur Lavin

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April 13, 2011

Is Sugar Toxic?

By GARY TAUBES

On May 26, 2009, Robert Lustig gave a lecture called “Sugar: The Bitter Truth,” which was posted on YouTube the following July. Since then, it has been viewed well over 800,000 times, gaining new viewers at a rate of about 50,000 per month, fairly remarkable numbers for a 90-minute discussion of the nuances of fructose biochemistry and human physiology.

Lustig is a specialist on pediatric hormone disorders and the leading expert in childhood obesity at the University of California, San Francisco, School of Medicine, which is one of the best medical schools in the country. He published his first paper on childhood obesity a dozen years ago, and he has been treating patients and doing research on the disorder ever since.

The viral success of his lecture, though, has little to do with Lustig’s impressive credentials and far more with the persuasive case he makes that sugar is a “toxin” or a “poison,” terms he uses together 13 times through the course of the lecture, in addition to the five references to sugar as merely “evil.” And by “sugar,” Lustig means not only the white granulated stuff that we put in coffee and sprinkle on cereal — technically known as sucrose — but also high-fructose corn syrup, which has already become without Lustig’s help what he calls “the most demonized additive known to man.”

It doesn’t hurt Lustig’s cause that he is a compelling public speaker. His critics argue that what makes him compelling is his practice of taking suggestive evidence and insisting that it’s incontrovertible. Lustig certainly doesn’t dabble in shades of gray. Sugar is not just an empty calorie, he says; its effect on us is much more insidious. “It’s not about the calories,” he says. “It has nothing to do with the calories. It’s a poison by itself.”

If Lustig is right, then our excessive consumption of sugar is the primary reason that the numbers of obese and diabetic Americans have skyrocketed in the past 30 years. But his argument implies more than that. If Lustig is right, it would mean that sugar is also the likely dietary cause of several other chronic ailments widely considered to be diseases of Western lifestyles — heart disease, hypertension and many common cancers among them.

The number of viewers Lustig has attracted suggests that people are paying attention to his argument. When I set out to interview public health authorities and researchers for this article, they would often initiate the interview with some variation of the comment “surely you’ve spoken to Robert Lustig,” not because Lustig has done any of the key research on sugar himself, which he hasn’t, but because he’s willing to insist publicly and unambiguously, when most researchers are not, that sugar is a toxic substance that people abuse. In Lustig’s view, sugar should be thought of, like cigarettes and alcohol, as something that’s killing us.

This brings us to the salient question: Can sugar possibly be as bad as Lustig says it is?

It’s one thing to suggest, as most nutritionists will, that a healthful diet includes more fruits and vegetables, and maybe less fat, red meat and salt, or less of everything. It’s entirely different to claim that one particularly cherished aspect of our diet might not just be an unhealthful indulgence but actually be toxic, that when you bake your children a birthday cake or give them lemonade on a hot summer day, you may be doing them more harm than good, despite all the love that goes with it. Suggesting that sugar might kill us is what zealots do. But Lustig, who has genuine expertise, has accumulated and synthesized a mass of evidence, which he finds compelling enough to convict sugar. His critics consider that evidence insufficient, but there’s no way to know who might be right, or what must be done to find out, without discussing it.

If I didn’t buy this argument myself, I wouldn’t be writing about it here. And I also have a disclaimer to acknowledge. I’ve spent much of the last decade doing journalistic research on diet and chronic disease — some of the more contrarian findings, on dietary fat, appeared in this magazine —– and I have come to conclusions similar to Lustig’s.

The history of the debate over the health effects of sugar has gone on far longer than you might imagine. It is littered with erroneous statements and conclusions because even the supposed authorities had no true understanding of what they were talking about. They didn’t know, quite literally, what they meant by the word “sugar” and therefore what the implications were.

So let’s start by clarifying a few issues, beginning with Lustig’s use of the word “sugar” to mean both sucrose — beet and cane sugar, whether white or brown — and high-fructose corn syrup. This is a critical point, particularly because high-fructose corn syrup has indeed become “the flashpoint for everybody’s distrust of processed foods,” says Marion Nestle, a New York University nutritionist and the author of “Food Politics.”

This development is recent and borders on humorous. In the early 1980s, high-fructose corn syrup replaced sugar in sodas and other products in part because refined sugar then had the reputation as a generally noxious nutrient. (“Villain in Disguise?” asked a headline in this paper in 1977, before answering in the affirmative.) High-fructose corn syrup was portrayed by the food industry as a healthful alternative, and that’s how the public perceived it. It was also cheaper than sugar, which didn’t hurt its commercial prospects. Now the tide is rolling the other way, and refined sugar is making a commercial comeback as the supposedly healthful alternative to this noxious corn-syrup stuff. “Industry after industry is replacing their product with sucrose and advertising it as such — ‘No High-Fructose Corn Syrup,’ ” Nestle notes.

But marketing aside, the two sweeteners are effectively identical in their biological effects. “High-fructose corn syrup, sugar — no difference,” is how Lustig put it in a lecture that I attended in San Francisco last December. “The point is they’re each bad — equally bad, equally poisonous.”

Refined sugar (that is, sucrose) is made up of a molecule of the carbohydrate glucose, bonded to a molecule of the carbohydrate fructose — a 50-50 mixture of the two. The fructose, which is almost twice as sweet as glucose, is what distinguishes sugar from other carbohydrate-rich foods like bread or potatoes that break down upon digestion to glucose alone. The more fructose in a substance, the sweeter it will be. High-fructose corn syrup, as it is most commonly consumed, is 55 percent fructose, and the remaining 45 percent is nearly all glucose. It was first marketed in the late 1970s and was created to be indistinguishable from refined sugar when used in soft drinks. Because each of these sugars ends up as glucose and fructose in our guts, our bodies react the same way to both, and the physiological effects are identical. In a 2010 review of the relevant science, Luc Tappy, a researcher at the University of Lausanne in Switzerland who is considered by biochemists who study fructose to be the world’s foremost authority on the subject, said there was “not the single hint” that H.F.C.S. was more deleterious than other sources of sugar.

The question, then, isn’t whether high-fructose corn syrup is worse than sugar; it’s what do they do to us, and how do they do it? The conventional wisdom has long been that the worst that can be said about sugars of any kind is that they cause tooth decay and represent “empty calories” that we eat in excess because they taste so good.

By this logic, sugar-sweetened beverages (or H.F.C.S.-sweetened beverages, as the Sugar Association prefers they are called) are bad for us not because there’s anything particularly toxic about the sugar they contain but just because people consume too many of them.

Those organizations that now advise us to cut down on our sugar consumption — the Department of Agriculture, for instance, in its recent Dietary Guidelines for Americans, or the American Heart Association in guidelines released in September 2009 (of which Lustig was a co-author) — do so for this reason. Refined sugar and H.F.C.S. don’t come with any protein, vitamins, minerals, antioxidants or fiber, and so they either displace other more nutritious elements of our diet or are eaten over and above what we need to sustain our weight, and this is why we get fatter.

Whether the empty-calories argument is true, it’s certainly convenient. It allows everyone to assign blame for obesity and, by extension, diabetes — two conditions so intimately linked that some authorities have taken to calling them “diabesity” — to overeating of all foods, or underexercising, because a calorie is a calorie. “This isn’t about demonizing any industry,” as Michelle Obama said about her Let’s Move program to combat the epidemic of childhood obesity. Instead it’s about getting us — or our children — to move more and eat less, reduce our portion sizes, cut back on snacks.

Lustig’s argument, however, is not about the consumption of empty calories — and biochemists have made the same case previously, though not so publicly. It is that sugar has unique characteristics, specifically in the way the human body metabolizes the fructose in it, that may make it singularly harmful, at least if consumed in sufficient quantities.

The phrase Lustig uses when he describes this concept is “isocaloric but not isometabolic.” This means we can eat 100 calories of glucose (from a potato or bread or other starch) or 100 calories of sugar (half glucose and half fructose), and they will be metabolized differently and have a different effect on the body. The calories are the same, but the metabolic consequences are quite different.

The fructose component of sugar and H.F.C.S. is metabolized primarily by the liver, while the glucose from sugar and starches is metabolized by every cell in the body. Consuming sugar (fructose and glucose) means more work for the liver than if you consumed the same number of calories of starch (glucose). And if you take that sugar in liquid form — soda or fruit juices — the fructose and glucose will hit the liver more quickly than if you consume them, say, in an apple (or several apples, to get what researchers would call the equivalent dose of sugar). The speed with which the liver has to do its work will also affect how it metabolizes the fructose and glucose.

In animals, or at least in laboratory rats and mice, it’s clear that if the fructose hits the liver in sufficient quantity and with sufficient speed, the liver will convert much of it to fat. This apparently induces a condition known as insulin resistance, which is now considered the fundamental problem in obesity, and the underlying defect in heart disease and in the type of diabetes, type 2, that is common to obese and overweight individuals. It might also be the underlying defect in many cancers.

If what happens in laboratory rodents also happens in humans, and if we are eating enough sugar to make it happen, then we are in trouble.

The last time an agency of the federal government looked into the question of sugar and health in any detail was in 2005, in a report by the Institute of Medicine, a branch of the National Academies. The authors of the report acknowledged that plenty of evidence suggested that sugar could increase the risk of heart disease and diabetes — even raising LDL cholesterol, known as the “bad cholesterol”—– but did not consider the research to be definitive. There was enough ambiguity, they concluded, that they couldn’t even set an upper limit on how much sugar constitutes too much. Referring back to the 2005 report, an Institute of Medicine report released last fall reiterated, “There is a lack of scientific agreement about the amount of sugars that can be consumed in a healthy diet.” This was the same conclusion that the Food and Drug Administration came to when it last assessed the sugar question, back in 1986. The F.D.A. report was perceived as an exoneration of sugar, and that perception influenced the treatment of sugar in the landmark reports on diet and health that came after.

The Sugar Association and the Corn Refiners Association have also portrayed the 1986 F.D.A. report as clearing sugar of nutritional crimes, but what it concluded was actually something else entirely. To be precise, the F.D.A. reviewers said that other than its contribution to calories, “no conclusive evidence on sugars demonstrates a hazard to the general public when sugars are consumed at the levels that are now current.” This is another way of saying that the evidence by no means refuted the kinds of claims that Lustig is making now and other researchers were making then, just that it wasn’t definitive or unambiguous.

What we have to keep in mind, says Walter Glinsmann, the F.D.A. administrator who was the primary author on the 1986 report and who now is an adviser to the Corn Refiners Association, is that sugar and high-fructose corn syrup might be toxic, as Lustig argues, but so might any substance if it’s consumed in ways or in quantities that are unnatural for humans. The question is always at what dose does a substance go from being harmless to harmful? How much do we have to consume before this happens?

When Glinsmann and his F.D.A. co-authors decided no conclusive evidence demonstrated harm at the levels of sugar then being consumed, they estimated those levels at 40 pounds per person per year beyond what we might get naturally in fruits and vegetables — 40 pounds per person per year of “added sugars” as nutritionists now call them. This is 200 calories per day of sugar, which is less than the amount in a can and a half of Coca-Cola or two cups of apple juice. If that’s indeed all we consume, most nutritionists today would be delighted, including Lustig.

But 40 pounds per year happened to be 35 pounds less than what Department of Agriculture analysts said we were consuming at the time — 75 pounds per person per year — and the U.S.D.A. estimates are typically considered to be the most reliable. By the early 2000s, according to the U.S.D.A., we had increased our consumption to more than 90 pounds per person per year.

That this increase happened to coincide with the current epidemics of obesity and diabetes is one reason that it’s tempting to blame sugars — sucrose and high-fructose corn syrup — for the problem. In 1980, roughly one in seven Americans was obese, and almost six million were diabetic, and the obesity rates, at least, hadn’t changed significantly in the 20 years previously. By the early 2000s, when sugar consumption peaked, one in every three Americans was obese, and 14 million were diabetic.

This correlation between sugar consumption and diabetes is what defense attorneys call circumstantial evidence. It’s more compelling than it otherwise might be, though, because the last time sugar consumption jumped markedly in this country, it was also associated with a diabetes epidemic.

In the early 20th century, many of the leading authorities on diabetes in North America and Europe (including Frederick Banting, who shared the 1923 Nobel Prize for the discovery of insulin) suspected that sugar causes diabetes based on the observation that the disease was rare in populations that didn’t consume refined sugar and widespread in those that did. In 1924, Haven Emerson, director of the institute of public health at Columbia University, reported that diabetes deaths in New York City had increased as much as 15-fold since the Civil War years, and that deaths increased as much as fourfold in some U.S. cities between 1900 and 1920 alone. This coincided, he noted, with an equally significant increase in sugar consumption — almost doubling from 1890 to the early 1920s — with the birth and subsequent growth of the candy and soft-drink industries.

Emerson’s argument was countered by Elliott Joslin, a leading authority on diabetes, and Joslin won out. But his argument was fundamentally flawed. Simply put, it went like this: The Japanese eat lots of rice, and Japanese diabetics are few and far between; rice is mostly carbohydrate, which suggests that sugar, also a carbohydrate, does not cause diabetes. But sugar and rice are not identical merely because they’re both carbohydrates. Joslin could not know at the time that the fructose content of sugar affects how we metabolize it.

Joslin was also unaware that the Japanese ate little sugar. In the early 1960s, the Japanese were eating as little sugar as Americans were a century earlier, maybe less, which means that the Japanese experience could have been used to support the idea that sugar causes diabetes. Still, with Joslin arguing in edition after edition of his seminal textbook that sugar played no role in diabetes, it eventually took on the aura of undisputed truth.

Until Lustig came along, the last time an academic forcefully put forward the sugar-as-toxin thesis was in the 1970s, when John Yudkin, a leading authority on nutrition in the United Kingdom, published a polemic on sugar called “Sweet and Dangerous.” Through the 1960s Yudkin did a series of experiments feeding sugar and starch to rodents, chickens, rabbits, pigs and college students. He found that the sugar invariably raised blood levels of triglycerides (a technical term for fat), which was then, as now, considered a risk factor for heart disease. Sugar also raised insulin levels in Yudkin’s experiments, which linked sugar directly to type 2 diabetes. Few in the medical community took Yudkin’s ideas seriously, largely because he was also arguing that dietary fat and saturated fat were harmless. This set Yudkin’s sugar hypothesis directly against the growing acceptance of the idea, prominent to this day, that dietary fat was the cause of heart disease, a notion championed by the University of Minnesota nutritionist Ancel Keys.

A common assumption at the time was that if one hypothesis was right, then the other was most likely wrong. Either fat caused heart disease by raising cholesterol, or sugar did by raising triglycerides. “The theory that diets high in sugar are an important cause of atherosclerosis and heart disease does not have wide support among experts in the field, who say that fats and cholesterol are the more likely culprits,” as Jane E. Brody wrote in The Times in 1977.

At the time, many of the key observations cited to argue that dietary fat caused heart disease actually support the sugar theory as well. During the Korean War, pathologists doing autopsies on American soldiers killed in battle noticed that many had significant plaques in their arteries, even those who were still teenagers, while the Koreans killed in battle did not. The atherosclerotic plaques in the Americans were attributed to the fact that they ate high-fat diets and the Koreans ate low-fat. But the Americans were also eating high-sugar diets, while the Koreans, like the Japanese, were not.

In 1970, Keys published the results of a landmark study in nutrition known as the Seven Countries Study. Its results were perceived by the medical community and the wider public as compelling evidence that saturated-fat consumption is the best dietary predictor of heart disease. But sugar consumption in the seven countries studied was almost equally predictive. So it was possible that Yudkin was right, and Keys was wrong, or that they could both be right. The evidence has always been able to go either way.

European clinicians tended to side with Yudkin; Americans with Keys. The situation wasn’t helped, as one of Yudkin’s colleagues later told me, by the fact that “there was quite a bit of loathing” between the two nutritionists themselves. In 1971, Keys published an article attacking Yudkin and describing his evidence against sugar as “flimsy indeed.” He treated Yudkin as a figure of scorn, and Yudkin never managed to shake the portrayal.

By the end of the 1970s, any scientist who studied the potentially deleterious effects of sugar in the diet, according to Sheldon Reiser, who did just that at the U.S.D.A.’s Carbohydrate Nutrition Laboratory in Beltsville, Md., and talked about it publicly, was endangering his reputation. “Yudkin was so discredited,” Reiser said to me. “He was ridiculed in a way. And anybody else who said something bad about sucrose, they’d say, ‘He’s just like Yudkin.’ ”

What has changed since then, other than Americans getting fatter and more diabetic? It wasn’t so much that researchers learned anything particularly new about the effects of sugar or high-fructose corn syrup in the human body. Rather the context of the science changed: physicians and medical authorities came to accept the idea that a condition known as metabolic syndrome is a major, if not themajor, risk factor for heart disease and diabetes. The Centers for Disease Control and Prevention now estimate that some 75 million Americans have metabolic syndrome. For those who have heart attacks, metabolic syndrome will very likely be the reason.

The first symptom doctors are told to look for in diagnosing metabolic syndrome is an expanding waistline. This means that if you’re overweight, there’s a good chance you have metabolic syndrome, and this is why you’re more likely to have a heart attack or become diabetic (or both) than someone who’s not. Although lean individuals, too, can have metabolic syndrome, and they are at greater risk of heart disease and diabetes than lean individuals without it.

Having metabolic syndrome is another way of saying that the cells in your body are actively ignoring the action of the hormone insulin — a condition known technically as being insulin-resistant. Because insulin resistance and metabolic syndrome still get remarkably little attention in the press (certainly compared with cholesterol), let me explain the basics.

You secrete insulin in response to the foods you eat — particularly the carbohydrates — to keep blood sugar in control after a meal. When your cells are resistant to insulin, your body (your pancreas, to be precise) responds to rising blood sugar by pumping out more and more insulin. Eventually the pancreas can no longer keep up with the demand or it gives in to what diabetologists call “pancreatic exhaustion.” Now your blood sugar will rise out of control, and you’ve got diabetes.

Not everyone with insulin resistance becomes diabetic; some continue to secrete enough insulin to overcome their cells’ resistance to the hormone. But having chronically elevated insulin levels has harmful effects of its own — heart disease, for one. A result is higher triglyceride levels and blood pressure, lower levels of HDL cholesterol (the “good cholesterol”), further worsening the insulin resistance — this is metabolic syndrome.

When physicians assess your risk of heart disease these days, they will take into consideration your LDL cholesterol (the bad kind), but also these symptoms of metabolic syndrome. The idea, according to Scott Grundy, a University of Texas Southwestern Medical Center nutritionist and the chairman of the panel that produced the last edition of the National Cholesterol Education Program guidelines, is that heart attacks 50 years ago might have been caused by high cholesterol — particularly high LDL cholesterol — but since then we’ve all gotten fatter and more diabetic, and now it’s metabolic syndrome that’s the more conspicuous problem.

This raises two obvious questions. The first is what sets off metabolic syndrome to begin with, which is another way of asking, What causes the initial insulin resistance? There are several hypotheses, but researchers who study the mechanisms of insulin resistance now think that a likely cause is the accumulation of fat in the liver. When studies have been done trying to answer this question in humans, says Varman Samuel, who studies insulin resistance at Yale School of Medicine, the correlation between liver fat and insulin resistance in patients, lean or obese, is “remarkably strong.” What it looks like, Samuel says, is that “when you deposit fat in the liver, that’s when you become insulin-resistant.”

That raises the other obvious question: What causes the liver to accumulate fat in humans? A common assumption is that simply getting fatter leads to a fatty liver, but this does not explain fatty liver in lean people. Some of it could be attributed to genetic predisposition. But harking back to Lustig, there’s also the very real possibility that it is caused by sugar.

As it happens, metabolic syndrome and insulin resistance are the reasons that many of the researchers today studying fructose became interested in the subject to begin with. If you want to cause insulin resistance in laboratory rats, says Gerald Reaven, the Stanford University diabetologist who did much of the pioneering work on the subject, feeding them diets that are mostly fructose is an easy way to do it. It’s a “very obvious, very dramatic” effect, Reaven says.

By the early 2000s, researchers studying fructose metabolism had established certain findings unambiguously and had well-established biochemical explanations for what was happening. Feed animals enough pure fructose or enough sugar, and their livers convert the fructose into fat — the saturated fatty acid, palmitate, to be precise, that supposedly gives us heart disease when we eat it, by raising LDL cholesterol. The fat accumulates in the liver, and insulin resistance and metabolic syndrome follow.

Michael Pagliassotti, a Colorado State University biochemist who did many of the relevant animal studies in the late 1990s, says these changes can happen in as little as a week if the animals are fed sugar or fructose in huge amounts — 60 or 70 percent of the calories in their diets. They can take several months if the animals are fed something closer to what humans (in America) actually consume — around 20 percent of the calories in their diet. Stop feeding them the sugar, in either case, and the fatty liver promptly goes away, and with it the insulin resistance.

Similar effects can be shown in humans, although the researchers doing this work typically did the studies with only fructose — as Luc Tappy did in Switzerland or Peter Havel and Kimber Stanhope did at the University of California, Davis — and pure fructose is not the same thing as sugar or high-fructose corn syrup. When Tappy fed his human subjects the equivalent of the fructose in 8 to 10 cans of Coke or Pepsi a day — a “pretty high dose,” he says —– their livers would start to become insulin-resistant, and their triglycerides would go up in just a few days. With lower doses, Tappy says, just as in the animal research, the same effects would appear, but it would take longer, a month or more.

Despite the steady accumulation of research, the evidence can still be criticized as falling far short of conclusive. The studies in rodents aren’t necessarily applicable to humans. And the kinds of studies that Tappy, Havel and Stanhope did — having real people drink beverages sweetened with fructose and comparing the effect with what happens when the same people or others drink beverages sweetened with glucose — aren’t applicable to real human experience, because we never naturally consume pure fructose. We always take it with glucose, in the nearly 50-50 combinations of sugar or high-fructose corn syrup. And then the amount of fructose or sucrose being fed in these studies, to the rodents or the human subjects, has typically been enormous.

This is why the research reviews on the subject invariably conclude that more research is necessary to establish at what dose sugar and high-fructose corn syrup start becoming what Lustig calls toxic. “There is clearly a need for intervention studies,” as Tappy recently phrased it in the technical jargon of the field, “in which the fructose intake of high-fructose consumers is reduced to better delineate the possible pathogenic role of fructose. At present, short-term-intervention studies, however, suggest that a high-fructose intake consisting of soft drinks, sweetened juices or bakery products can increase the risk of metabolic and cardiovascular diseases.”

In simpler language, how much of this stuff do we have to eat or drink, and for how long, before it does to us what it does to laboratory rats? And is that amount more than we’re already consuming?

Unfortunately, we’re unlikely to learn anything conclusive in the near future. As Lustig points out, sugar and high-fructose corn syrup are certainly not “acute toxins” of the kind the F.D.A. typically regulates and the effects of which can be studied over the course of days or months. The question is whether they’re “chronic toxins,” which means “not toxic after one meal, but after 1,000 meals.” This means that what Tappy calls “intervention studies” have to go on for significantly longer than 1,000 meals to be meaningful.

At the moment, the National Institutes of Health are supporting surprisingly few clinical trials related to sugar and high-fructose corn syrup in the U.S. All are small, and none will last more than a few months. Lustig and his colleagues at U.C.S.F. — including Jean-Marc Schwarz, whom Tappy describes as one of the three best fructose biochemists in the world — are doing one of these studies. It will look at what happens when obese teenagers consume no sugar other than what they might get in fruits and vegetables. Another study will do the same with pregnant women to see if their babies are born healthier and leaner.

Only one study in this country, by Havel and Stanhope at the University of California, Davis, is directly addressing the question of how much sugar is required to trigger the symptoms of insulin resistance and metabolic syndrome. Havel and Stanhope are having healthy people drink three sugar- or H.F.C.S.-sweetened beverages a day and then seeing what happens. The catch is that their study subjects go through this three-beverage-a-day routine for only two weeks. That doesn’t seem like a very long time — only 42 meals, not 1,000 — but Havel and Stanhope have been studying fructose since the mid-1990s, and they seem confident that two weeks is sufficient to see if these sugars cause at least some of the symptoms of metabolic syndrome.

So the answer to the question of whether sugar is as bad as Lustig claims is that it certainly could be. It very well may be true that sugar and high-fructose corn syrup, because of the unique way in which we metabolize fructose and at the levels we now consume it, cause fat to accumulate in our livers followed by insulin resistance and metabolic syndrome, and so trigger the process that leads to heart disease, diabetes and obesity. They could indeed be toxic, but they take years to do their damage. It doesn’t happen overnight. Until long-term studies are done, we won’t know for sure.

One more question still needs to be asked, and this is what my wife, who has had to live with my journalistic obsession on this subject, calls the Grinch-trying-to-steal-Christmas problem. What are the chances that sugar is actually worse than Lustig says it is?

One of the diseases that increases in incidence with obesity, diabetes and metabolic syndrome is cancer. This is why I said earlier that insulin resistance may be a fundamental underlying defect in many cancers, as it is in type 2 diabetes and heart disease. The connection between obesity, diabetes and cancer was first reported in 2004 in large population studies by researchers from the World Health Organization’s International Agency for Research on Cancer. It is not controversial. What it means is that you are more likely to get cancer if you’re obese or diabetic than if you’re not, and you’re more likely to get cancer if you have metabolic syndrome than if you don’t.

This goes along with two other observations that have led to the well-accepted idea that some large percentage of cancers are caused by our Western diets and lifestyles. This means they could actually be prevented if we could pinpoint exactly what the problem is and prevent or avoid that.

One observation is that death rates from cancer, like those from diabetes, increased significantly in the second half of the 19th century and the early decades of the 20th. As with diabetes, this observation was accompanied by a vigorous debate about whether those increases could be explained solely by the aging of the population and the use of new diagnostic techniques or whether it was really the incidence of cancer itself that was increasing. “By the 1930s,” as a 1997 report by the World Cancer Research Fund International and the American Institute for Cancer Research explained, “it was apparent that age-adjusted death rates from cancer were rising in the U.S.A.,” which meant that the likelihood of any particular 60-year-old, for instance, dying from cancer was increasing, even if there were indeed more 60-years-olds with each passing year.

The second observation was that malignant cancer, like diabetes, was a relatively rare disease in populations that didn’t eat Western diets, and in some of these populations it appeared to be virtually nonexistent. In the 1950s, malignant cancer among the Inuit, for instance, was still deemed sufficiently rare that physicians working in northern Canada would publish case reports in medical journals when they did diagnose a case.

In 1984, Canadian physicians published an analysis of 30 years of cancer incidence among Inuit in the western and central Arctic. While there had been a “striking increase in the incidence of cancers of modern societies” including lung and cervical cancer, they reported, there were still “conspicuous deficits” in breast-cancer rates. They could not find a single case in an Inuit patient before 1966; they could find only two cases between 1967 and 1980. Since then, as their diet became more like ours, breast cancer incidence has steadily increased among the Inuit, although it’s still significantly lower than it is in other North American ethnic groups. Diabetes rates in the Inuit have also gone from vanishingly low in the mid-20th century to high today.

Now most researchers will agree that the link between Western diet or lifestyle and cancer manifests itself through this association with obesity, diabetes and metabolic syndrome — i.e., insulin resistance. This was the conclusion, for instance, of a 2007 report published by the World Cancer Research Fund and the American Institute for Cancer Research — “Food, Nutrition, Physical Activity and the Prevention of Cancer.”

So how does it work? Cancer researchers now consider that the problem with insulin resistance is that it leads us to secrete more insulin, and insulin (as well as a related hormone known as insulin-like growth factor) actually promotes tumor growth.

As it was explained to me by Craig Thompson, who has done much of this research and is now president of Memorial Sloan-Kettering Cancer Center in New York, the cells of many human cancers come to depend on insulin to provide the fuel (blood sugar) and materials they need to grow and multiply. Insulin and insulin-like growth factor (and related growth factors) also provide the signal, in effect, to do it. The more insulin, the better they do. Some cancers develop mutations that serve the purpose of increasing the influence of insulin on the cell; others take advantage of the elevated insulin levels that are common to metabolic syndrome, obesity and type 2 diabetes. Some do both. Thompson believes that many pre-cancerous cells would never acquire the mutations that turn them into malignant tumors if they weren’t being driven by insulin to take up more and more blood sugar and metabolize it.

What these researchers call elevated insulin (or insulin-like growth factor) signaling appears to be a necessary step in many human cancers, particularly cancers like breast and colon cancer. Lewis Cantley, director of the Cancer Center at Beth Israel Deaconess Medical Center at Harvard Medical School, says that up to 80 percent of all human cancers are driven by either mutations or environmental factors that work to enhance or mimic the effect of insulin on the incipient tumor cells. Cantley is now the leader of one of five scientific “dream teams,” financed by a national coalition called Stand Up to Cancer, to study, in the case of Cantley’s team, precisely this link between a specific insulin-signaling gene (known technically as PI3K) and tumor development in breast and other cancers common to women.

Most of the researchers studying this insulin/cancer link seem concerned primarily with finding a drug that might work to suppress insulin signaling in incipient cancer cells and so, they hope, inhibit or prevent their growth entirely. Many of the experts writing about the insulin/cancer link from a public health perspective — as in the 2007 report from the World Cancer Research Fund and the American Institute for Cancer Research — work from the assumption that chronically elevated insulin levels and insulin resistance are both caused by being fat or by getting fatter. They recommend, as the 2007 report did, that we should all work to be lean and more physically active, and that in turn will help us prevent cancer.

But some researchers will make the case, as Cantley and Thompson do, that if something other than just being fatter is causing insulin resistance to begin with, that’s quite likely the dietary cause of many cancers. If it’s sugar that causes insulin resistance, they say, then the conclusion is hard to avoid that sugar causes cancer — some cancers, at least — radical as this may seem and despite the fact that this suggestion has rarely if ever been voiced before publicly. For just this reason, neither of these men will eat sugar or high-fructose corn syrup, if they can avoid it.

“I have eliminated refined sugar from my diet and eat as little as I possibly can,” Thompson told me, “because I believe ultimately it’s something I can do to decrease my risk of cancer.” Cantley put it this way: “Sugar scares me.”

Sugar scares me too, obviously. I’d like to eat it in moderation. I’d certainly like my two sons to be able to eat it in moderation, to not overconsume it, but I don’t actually know what that means, and I’ve been reporting on this subject and studying it for more than a decade. If sugar just makes us fatter, that’s one thing. We start gaining weight, we eat less of it. But we are also talking about things we can’t see — fatty liver, insulin resistance and all that follows. Officially I’m not supposed to worry because the evidence isn’t conclusive, but I do.

Gary Taubes (gataubes@gmail.com) is a Robert Wood Johnson Foundation independent investigator in health policy and the author of “Why We Get Fat.” Editor: Vera Titunik (v.titunik-MagGroup@nytimes.com).

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