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Dean Pomerleau

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About Dean Pomerleau

  • Birthday 11/12/1964

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  1. Dean Pomerleau

    Coffee Revisited

    If you've gotten your (partial) genome sequenced via 23andMe, you can check if you are a fast or slow caffeine metabolize via this link. If your genotype is A/A for the SNP rs762551 (like mine), you are a "fast metabolizer" of caffeine and are likely to enjoy the positive effects of coffee consumption that Dr. Greger discusses. --Dean
  2. Dean Pomerleau

    Watch out for fish, especially fatty, like salmon

    Saul, Why is it you speak so authoritatively on subjects about which you appear to know so little? From https://en.m.wikipedia.org/wiki/Yellowfin_tuna: Rhetorical question... Dean
  3. Saul, Gordo is right and you've mischaracterized Luigi's perspective. Luigi doesn't believe "severe CR" is wise for humans. Here is an excerpt from my report of the private discussion he and I had on my visit to WUSTL for his human CR study in 2013, when I was practicing what most people (except Michael) would consider reasonably "severe" CR (BMI ~17.5): When I asked questions about "how low is too low?" (with regard to IGF-1, BMI, or any biomarkers of successful CR) he [Luigi] repeatedly said that we just don't know, even for rodents, to say nothing of people. He said recent data in another lab suggests different strains of mice respond differently to CR - some live longest on 40% CR (and don't live as long with more severe CR) while others live longest all the way up to 70% CR. He said if he had the money, he'd do studies to determine what biomarkers are indicative of an animal being in the CR "sweet spot", but alas he lamented that NIH funding goes more to yeast and biochemical pathway research than seemingly more informative animal and human experiments. Funding he says is tough for his kind of research, but he's getting by on some government grants and some private funding. But if he had to guess, he said I'm taking a risk being as low as I am in some of the markers (particularly IGF-1), and thought it would be wise to gain some weight. He said it would be safer, and referred, for example, to difficulty I might experience recovering from an accident (e.g. car crash) that might make it hard for me to volitionally gain or maintain weight necessary to heal (e.g. if in coma or otherwise impaired state). --Dean
  4. Hi Saul, While your osteoporosis may indeed pre-date your practice of CR, you've previously shared that your bone density "plummeted" when you switched from one osteoporosis treatment to another after being on your version of serious CR for over a decade. You've also acknowledged that "... it's certainly true that CR is a negative for osteo." I would hope not. You've been on daily injections of Forteo to maintain your bones for something like 15 year. Maybe in part. But I strongly suspect Gordo is also referring to your fellow serious CRer Al Pater, who has a long history of osteoporosis, dramatic height loss and serious fractures. We've had this debate about CR's impact on bone health many times before. The upshot seems to be: 1) There is strong evidence CR reduces bone mass and bone density. 2) CR with "optimal nutrition" (whatever that means) may help preserve bone quality, perhaps mitigating CR's impact on fracture risk. 3) Impact-oriented exercise and/or resistance training likely helps CR folks maintain bone health. --Dean
  5. Saul, This seems a bit disingenuous given your own (past?) issues with osteoporosis and extensive treatment for it, e.g: https://www.crsociety.org/topic/11657-cr-and-osteoporosis/?do=findComment&comment=19874 --Dean
  6. Dean Pomerleau

    98.6 F (37.0 C) is old school

    Hi Matt (and Saul)! Here is what happened to Warren: --Dean
  7. Saul, If you read Al's first (2012) paper, you'll see that it was a more careful analysis of the data from the second (2007) paper, along with more data from the same population of European men, including a longer follow-up and hence more cases of prostate cancer (1542 vs. 630) among the men they've been following in EPIC. It looks like (unsurprisingly) higher total and free IGF-1 is positively correlated with later diagnosis of prostate cancer in this population. --Dean
  8. Hi folks, It's been a while, but I just had to comment on this study [1] posted by Al Pater (thanks Al!) on the connection between CR, brown/beige fat and cold exposure, particularly since it can be seen as supporting an idea I speculated way back in this post, which can be summarized as follows: This study [1] found that CR does indeed induce the browning of white fat. This was true when the CR mice were housed at thermoneutral temperature (30°C = 86°F), and even more so when they were housed at normal room temperature (which is pretty chilly for mice). This extra beige fat allowed the CR mice to maintain their body temperature better than AL-fed mice when both were exposed to cold (6°C = 43°F) for 12 hours. The extra beige fat also dramatically improved the CR'd mice insulin sensitivity, and this was true for both seriously CRed mice (40% CR) and less dramatically CRed mice (20% CR). When the CR mice were prevented from developing beige fat (via genetic manipulation), their improved glucose tolerance and cold tolerance disappeared. In the discussion section, the authors address the paradox I discussed previously, namely why should animals increase the amount of calorie-burning beige fat when food is scarce, rather than conserving every calorie they can to tide them over the lean times? Here is what they say (emphasis mine): "Browning of the fat depots enhances energy dissipation and reduces the overall adiposity, thereby contributing to the overall fat decrease during CR. Cold exposure and long-term endurance exercise are physiological stimuli that increase the browning (van Marken Lichtenbelt et al., 2009; Harms and Seale, 2013; Wu et al., 2012, 2013; Bostrom et al., 2012). The increased energy dissipation during cold exposure is physiologically justified by the need for increased heat production as a defense against hypothermia. The increased browning during exercise, on the other hand, seems paradoxical, and one explanation was that it might have evolved as a consequence of muscle contraction during shivering (Bostrom et al., 2012). We note that a common feature between the cold exposure and endurance exercise is the negative energy balance: higher energy expenditure than intake leading to fat loss. In addition, interventional microbiota depletion, either by means of antibiotics administration or in germ-free mice (Sua´rez-Zamorano et al., 2015; Chevalier et al., 2015), as well as RYGB (Neinast et al., 2015) also increase the browning to a similar extent as several endurance exercise regimens. These are also conditions of decreased caloric uptake and negative energy balance. Seen in this context, our results that CR promotes the development of functional beige fat provide insights into the regulation of the overall energy homeostasis during energy scarcity, and they suggest that white fat browning is a common feature of conditions of negative energy balance." In short, they don't really try to explain the paradox, simply observing that under a wide range of conditions that result in a negative energy balance (including cold exposure, exercise and CR), the result is increased browning of white fat, along with other metabolic improvements, including improved glucose tolerance. Unfortunately for us, the browning of fat is more readily accomplished by rodents than humans, which probably explains why many of us have reported worse glucose control when practicing serious CR (without cold exposure). I stand by my hypothesis, that CR and cold exposure likely co-occurred in the evolutionary past of our mammalian ancestors, so they evolved a synergistic response to the combination which is better preserved in rodents than humans. We humans may be able to trigger a similar beneficial response, but it likely requires the combination of CR and cold exposure to boost browning of white fat like observed in CRed rodents. --Dean ------------------------ [1] Cell Metab. 2016 Sep 13;24(3):434-446. doi: 10.1016/j.cmet.2016.07.023. Epub 2016 Aug 25. Caloric Restriction Leads to Browning of White Adipose Tissue through Type 2 Immune Signaling. Fabbiano S(1), Suárez-Zamorano N(1), Rigo D(1), Veyrat-Durebex C(1), Stevanovic Dokic A(1), Colin DJ(2), Trajkovski M(3). Free Full text: https://www.cell.com/cell-metabolism/pdfExtended/S1550-4131(16)30374-6 Caloric restriction (CR) extends lifespan from yeast to mammals, delays onset of age-associated diseases, and improves metabolic health. We show that CR stimulates development of functional beige fat within the subcutaneous and visceral adipose tissue, contributing to decreased white fat and adipocyte size in lean C57BL/6 and BALB/c mice kept at room temperature or at thermoneutrality and in obese leptin-deficient mice. These metabolic changes are mediated by increased eosinophil infiltration, type 2 cytokine signaling, and M2 macrophage polarization in fat of CR animals. Suppression of the type 2 signaling, using Il4ra(-/-), Stat6(-/-), or mice transplanted with Stat6(-/-) bone marrow-derived hematopoietic cells, prevents the CR-induced browning and abrogates the subcutaneous fat loss and the metabolic improvements induced by CR. These results provide insights into the overall energy homeostasis during CR, and they suggest beige fat development as a common feature in conditions of negative energy balance. Copyright © 2016 Elsevier Inc. All rights reserved. DOI: 10.1016/j.cmet.2016.07.023 PMID: 27568549
  9. Hi James! I bite about 1/6th of this 100mcg Solgars B12 supplement per day to get a small multiple of the RDA. https://www.amazon.com/dp/B00014E9W0/ref=cm_sw_r_cp_taa_FwDCBbCW342NE --Dean
  10. Tom, All very good points. Coincidentally, my wife and I just met with our financial adviser and talked to him about long-term care insurance. My wife is particularly concerned because several of her family have suffered from Alzheimer's and so she is worried for herself and knows how expensive long-term care can be. He's going to get us quotes for the costs and benefits of signing up soon (e.g. Around 55) vs waiting until 60 or 65, as well as all the various options (different levels of monthly payout, duration of coverage, inflation protection etc). Have you (Tom) or any other "old-timers" looked into or signed up for long-term care insurance? --Dean
  11. I did a little more digging and found more about Ralph on this very interesting, if outdated, web page about the science of CR. Here is what it says: In 1956, at the age of 53, Ralph Cornell (left), of Massilon, Ohio, began skipping lunch. From then on, he became voluntarily calorie restricted. On March 13, 2006, Mr. Cornell celebrated his 103rd birthday. He continued to drive every day to and from his real estate business until he was 101. At that time, he fell on his front porch and broke his hip (osteoporosis?) He then retired from his real estate operations. Ralph has now outlived all his siblings, including his sister, Edna, who died recently at 93. (Many members of Ralph's family have lived into their 90's.) In addition to his broken hip, Ralph has also suffered from a serious heart attack. Still, he couldn't have known until fairly recently what's now known about the nutritional requirements unique to CR. Also, his heart disease might have been preventable given early attention. Note that Ralph is reading. If you're 25, you may think, "So what?", but if you're 80 or 90, you'll realize that at 103, most people can't read. Ralph is the Neil Armstrong of calorie restriction. While we can't draw too much from what happens to one man, or two or three, it's encouraging that what is happening is consistent with what we might expect CR to accomplish in humans. Ralph has been a close friend of Paul McGlothin and Meredith Averill for many years. June 7, 2008 Update: Ralph Cornell celebrated his 104th birthday on March 13, 2007, but I don't see any indications that he was still alive for his 105th birthday in 2008. Still he had quite a life, and was still enjoying it at 104 (when he attended a football game). (He certainly doesn't look like the typical centenarian in this picture.) He had a very serious heart attack a few years ago. It's my impression that he avoided doctors, and of course, some of the recent ideas regarding nutrition for the calorie-restricted wouldn't have been available to him until recently. CR begun at the age of 53 probably added 10 years to his life span and allowed him to drive to and from his office until he was 101. Here is the picture of Ralph referenced above: He does look pretty good for 103! --Dean
  12. Gordo, Let me play a bit of devil's advocate, just for the fun of it :-). You wrote: To give credit where credit is due, Michael is perhaps the one among us who isn't just rearranging deck chairs with idle debate, since he is directly involved in SENS's efforts to do something about aging. Putting our disagreements regarding the finer points about CR efficacy & translatability aside, Michael deserves huge kudos for his efforts at SENS, and the more we distract him the less he can contribute to actually solving the problem of aging! Yes, here is a link to the discussion of one controversial study (Nelson [1]) showing the effectiveness of CR varies dramatically with mouse strain, which Michael has suggested we should ignore since he says a good fraction of the mutant strains in [1] are seriously messed up. Yes, but even more interestingly, evidence suggests that mice engineered to have more brown fat and a higher than normal body temperature as a result, have increased mean and maximal lifespan independent of calorie restriction. See this recent post in the cold exposure thread. I don't know of any CR Society members who've been doing CR for long enough to approach centenarian status. While Walford's original "The 120 Year Diet" book was first published in 1987, the CR Society didn't really get off the ground until the mid 90s. That means there's only been a little over 20 years during which someone could be expected to be intentionally practicing CR for life extension. For someone who started 20 years ago to make it to 100, they'd have to have been approaching 80 when they started (obviously). But anyone starting CR at 80 is unlikely to see much life extension benefit since benefits are proportional to the fraction of one's life spent under CR, and because late life CR is apt to hurt survival as much as help, as we've discussed on other threads. But having said that, there is one anecdote I've heard about someone recently reaching centenarian status subsequent to long term CR - Paul McGlothin's friend Ralph. I can't independently verify what Paul claims about Ralph and his CR practice since I've only heard of him through Paul, but here is what Paul says about Ralph in this Humanity+ article: Closer to home, the longest-lived member of the CR Society, Ralph Cornell, followed that same philosophy. He said his most important exercise was the Thumb Exercise: He pushed himself away from the table with his thumbs when he started to get full. And he lived 104 healthy years. So there is one anecdote of impressive human longevity for a CR practitioner (edit - see below for more details on Ralph). --Dean --------------------- 1] Aging Cell. 2010 Feb;9(1):92-5. doi: 10.1111/j.1474-9726.2009.00533.x. Epub 2009 Oct 30. Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. Liao CY(1), Rikke BA, Johnson TE, Diaz V, Nelson JF. Author information: (1)Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. Comment in Aging Cell. 2010 Jun;9(3):448-9; discussion 450-2. Chronic dietary restriction (DR) is considered among the most robust life-extending interventions, but several reports indicate that DR does not always extend and may even shorten lifespan in some genotypes. An unbiased genetic screen of the lifespan response to DR has been lacking. Here, we measured the effect of one commonly used level of DR (40% reduction in food intake) on mean lifespan of virgin males and females in 41 recombinant inbred strains of mice. Mean strain-specific lifespan varied two to threefold under ad libitum (AL) feeding and 6- to 10-fold under DR, in males and females respectively. Notably, DR shortened lifespan in more strains than those in which it lengthened life. Food intake and female fertility varied markedly among strains under AL feeding, but neither predicted DR survival: therefore, strains in which DR shortened lifespan did not have low food intake or poor reproductive potential. Finally, strain-specific lifespans under DR and AL feeding were not correlated, indicating that the genetic determinants of lifespan under these two conditions differ. These results demonstrate that the lifespan response to a single level of DR exhibits wide variation amenable to genetic analysis. They also show that DR can shorten lifespan in inbred mice. Although strains with shortened lifespan under 40% DR may not respond negatively under less stringent DR, the results raise the possibility that life extension by DR may not be universal. PMCID: PMC3476836 PMID: 19878144
  13. Thanks Michael, Nice post. I think we agree about quite a few things about the article I discussed (Mitchell [1]): It seemed to go against conventional wisdom, namely that more severe CR (CR40) usually beats less severe CR (CR20) at least in this strain of mouse. Mitchell [1] didn't appear to do anything obviously wrong in their methodology / animal husbandry that would explain their results. The longevity of the AL groups in Mitchell [1] compares favorably with AL groups in other studies, supporting the idea they weren't messing up care of the animals. Several of the studies you cited to support CR40 benefits either started CR immediately after weaning, and most of the rest that started post-weaning didn't start quite as late as the 6 month point that Michell [1] started at. None of the studies you cited also had a moderate CR comparison group, i.e. your posted studies showed that CR40 extends lifespan, rather than comparing several degrees of CR within the same strain for their relative effectiveness. You said: I'm not saying CR40 doesn't work. I'm just saying it might not be as robust a result as we've been assuming, and in some instances CR20 may work comparably well, and perhaps even better. None of your posted studies actually showed CR40 resulted in increased longevity relative to a moderate CR group within the same experiment, and cross-study results are notoriously hard to interpret, since so many things can impact results. But one cross-study observation I would like to point out is between my study Mitchell [1] and the study you cite as Sun [10]. Both were in a similar (although not identical) strains of mice (C57BL/6J vs. C57BL6x129SV). Mitchell [1] started its mice on CR at 6 months (approx. human equiv of 30 years old) while Sun [10] started CR at 3 months (~human teenager). I've rearranged the graphs you posted from [10], erased the growth-hormone knockout groups from the graphs, and posted them below the corresponding graphs from Mitchell [1]. The Mitchell [1] graphs are in the top row and the Sun [10] graphs are in the bottom row: Looking at the lifespan graphs on the left side, the AL-fed females (first column) in both groups has a max lifespan of about 140 weeks, and the both groups of males (second column) also had maximum lifespans of about 140 weeks. So a pretty good baseline match between the two studies. We also see the lifespan benefits of CR40 (red curves in all graphs) is somewhat more robust in males than females. In particular, early deaths in the female CR40 group took its toll in both studies. In the males, CR40 showed a robust and comparable life extension benefit in both studies. It's just that CR20 males in Mitchell (blue line in second column in top row) did even better than the CR40 male mice. But what I find most interesting is the weight trajectories in the two studies, shown in the right two columns. In both sexes, the CR40 mice in Sun [10] (lower two graphs on the right) started out at CR onset weighing less than their counterparts in Mitchell [1] (top two graphs on the right), which isn't surprising, since they were half the age of the mice in Mitchell (3mo vs. 6mo) at CR onset. Even more interesting the Sun [10] CR40 mice continued to gradually gain weight throughout most of their life, until the very end of life when it started to drop. In contrast, the CR40 mice in Mitchell had a pretty precipitous drop in weight right after CR onset and if anything drifted somewhat downward in their weight throughout their lives. In fact, the CR40 mice in Mitchell started out heavier (since they were older at CR onset) but eventually dropped below the weight of the CR40 mice in Sun [10]. Further, the weight trajectory and maximum adult weight of the CR20 mice in Mitchell [1] look a lot more like the CR40 mice in Sun [10]. If I had to guess what is going on, I would say that the stress of CR40 was well-tolerated when the onset was in adolescence (i.e. Sun [10]), moderating the mice's growth and keeping them lean throughout their adult life. But started CR40 in young adulthood (i.e. Mitchell [1]) once the mice had reached maturity, was more severe than was optimal for the mice, causing them to lose weight initially and be less robust and long-lived relative to their less severely CR'ed counterparts (the CR20 mice). It was really interesting to me to see those CR40 weight trajectories in Sun [10]. The fact that these animals continued to gain weight after CR40 was initiated, just more slowly than the AL group, really shows me how different human CR is, at least a commonly practiced. That is, at least for most of us, we started CR well past when we were fully grown, and lost a substantial amount of weight after going on CR. In this sense we humans are much more like the Mitchell CR40 mice in terms of our weight trajectory than the Sun CR40 mice. If this is true, the moral would seem to be that if you start CR early, you can tolerate and benefit from more severe CR. If you start later, and in particular if CR results in a dramatic weight loss, you might not be doing yourself a big favor. Better to find a target calorie level that keeps you lean and your weight stable than to cut calories to the bone and become very skinny, especially if you start CR in middle age like most of us. P.S. I agree that my tone in earlier posts has sometimes been more caustic than it should have been. I apologize for that. --Dean --------- [1] Cell Metab. 2016 Jun 14;23(6):1093-112. doi: 10.1016/j.cmet.2016.05.027. Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice. Mitchell SJ, Madrigal-Matute J(2), Scheibye-Knudsen M(3), Fang E(4), Aon M(5), González-Reyes JA(6), Cortassa S(5), Kaushik S(2), Gonzalez-Freire M, Patel B(2), Wahl D, Ali A, Calvo-Rubio M(6), Burón MI(6), Guiterrez V, Ward TM, Palacios HH, Cai H(7), Frederick DW(8), Hine C(9), Broeskamp F(10), Habering L(10), Dawson J, Beasley TM, Wan J(12), Ikeno Y(13), Hubbard G(13), Becker KG(14), Zhang Y(14), Bohr VA(4), Longo DL(14), Navas P(15), Ferrucci L, Sinclair DA, Cohen P(12), Egan JM(7), Mitchell JR(9), Baur JA(8), Allison DB, Anson RM, Villalba JM(6), Madeo F(10), Cuervo AM(2), Pearson KJ(17), Ingram DK(18), Bernier M, de Cabo R(19). Free full text: http://www.sciencedi...550413116302492 PMID: 27304509 --------- 10: Sun LY, Spong A, Swindell WR, Fang Y, Hill C, Huber JA, Boehm JD, Westbrook R, Salvatori R, Bartke A. Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. Elife. 2013 Oct 29;2:e01098. doi: 10.7554/eLife.01098. PubMed PMID: 24175087; PubMed Central PMCID: PMC3810783.
  14. All, This new study [1] (free full text) looks to me to be the best direct evidence so far that the underlying premise of this entire thread is correct, namely that the brown adipose tissue (BAT) induced by consistent cold exposure can improve both healthspan and lifespan, independent of calorie restriction. The authors created a mutant strain of standard C57Bl6/J mice that produced more BAT by knocking out a particular gene (RGS14). They fed both the knockout mice and wild-type mice ad-lib for life, and measured a bunch of things including lifespan. The BAT-boosted mice lived 10% longer (both mean and maximum lifespan), and had much healthier appearance to boot relative to the unmodified (WT) mice. Here is the survival graph along with pictures of the wild type mice (WT), BAT-boosted knockout mice (RGS14 KO) and "BAT Recipient" mice: Notice the WT mouse on the left looks old, grey and balding. The "BAT Recipient" mouse has a nice, smooth, dark shiny coat, just like the knockout mouse. The "BAT recipients" mice in the study were WT mice that received a BAT transplant at 3-4 months of age, to simulate the effects of the RGS14 knockout (i.e. boosting the amount of BAT). Many of the same metabolic and phenotypic changes were observed in the BAT transplant mice as was seen in the knockout mice. Unfortunately they didn't report the lifespan of the BAT transplant mice. Some caution is in order however. First, as far as I can tell those aren't stellar lifespans for either the WT or knockout mice. Plus the authors didn't report food intake. Also, the knockout mice with genetically more BAT weighed slightly less than the WT mice, but this is unlikely to be a "crypto-CR" effect, since the knockout mice had an increased metabolic rate (eyeballing Fig 2e, about 10-15% higher metabolic rate), and so were presumably eating and burning more calories than the WT mice. --Dean ---------------------- [1] Aging Cell. 2018 Apr 14:e12751. doi: 10.1111/acel.12751. [Epub ahead of print] Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14. Vatner DE(1), Zhang J(1), Oydanich M(1), Guers J(1), Katsyuba E(2), Yan L(1), Sinclair D(3), Auwerx J(2), Vatner SF(1). Author information: (1)Department of Cell Biology & Molecular Medicine, Rutgers University-New Jersey Medical School, Newark, NJ, USA. (2)Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. (3)Department of Genetics, Harvard Medical School, Boston, MA, USA. free full text: https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.12751 Disruption of the regulator for G protein signaling 14 (RGS14) knockout (KO) in mice extends their lifespan and has multiple beneficial effects related to healthful aging, that is, protection from obesity, as reflected by reduced white adipose tissue, protection against cold exposure, and improved metabolism. The observed beneficial effects were mediated by improved mitochondrial function. But most importantly, the main mechanism responsible for the salutary properties of the RGS14 KO involved an increase in brown adipose tissue (BAT), which was confirmed by surgical BAT removal and transplantation to wild-type (WT) mice, a surgical simulation of a molecular knockout. This technique reversed the phenotype of the RGS14 KO and WT, resulting in loss of the improved metabolism and protection against cold exposure in RGS14 KO and conferring this protection to the WT BAT recipients. Another mechanism mediating the salutary features in the RGS14 KO was increased SIRT3. This mechanism was confirmed in the RGS14 X SIRT3 double KO, which no longer demonstrated improved metabolism and protection against cold exposure. Loss of function of the Caenorhabditis elegans RGS-14 homolog confirmed the evolutionary conservation of this mechanism. Thus, disruption of RGS14 is a model of healthful aging, as it not only enhances lifespan, but also protects against obesity and cold exposure and improves metabolism with a key mechanism of increased BAT, which, when removed, eliminates the features of healthful aging. DOI: 10.1111/acel.12751 PMID: 29654651
  15. Dean Pomerleau

    Zero-energy Thickeners

    Psyllium powder is an a cheaper fiber-only alternative thickener you might try. --Dean