From owner-ageing@net.bio.net Sat Oct 03 23:00:00 1992 Path: biosci!uwm.edu!spool.mu.edu!sdd.hp.com!news.cs.indiana.edu!nstn.ns.ca!ac.dal.ca!bthill From: bthill@ac.dal.ca Newsgroups: bionet.molbio.ageing Subject: Michael Rose Message-ID: <1992Oct4.152120.7945@ac.dal.ca> Date: 4 Oct 92 18:21:20 GMT Organization: Dalhousie University, Halifax, Nova Scotia, Canada Lines: 4 Is Michael Rose out there? I recently saw him on CNN and he appears to be getting younger since he moved to California. Brian Hill, email bthill@ac.dal.ca From owner-ageing@net.bio.net Wed Oct 07 23:00:00 1992 Path: biosci!CU.NIH.GOV!CZJ From: CZJ@CU.NIH.GOV Newsgroups: bionet.molbio.ageing Subject: Re: Chelation therapy and iron [was Re: Have you heard of this?????] Message-ID: <9210082046.AA12073@net.bio.net> Date: 8 Oct 92 20:44:48 GMT Sender: daemon@net.bio.net Distribution: bionet Lines: 67 > In article <1992Oct5.170349.19325@spdcc.com> dyer@spdcc.com (Steve Dyer) writes: > >In article <1992Oct5.121701.392@lrc.edu> dorham_r@lrc.edu writes: > >>I would like to know if anyone has heard of chelation therapy. If > >>anyone has, could you tell me something about it? Thanks!!!! > > > >Well, there are two kinds of "chelation therapy": are you interested in > >the bozoid one that people push to "treat" heart disease, or the legitimate > >therapy used to remove heavy metals like lead and mercury from the body in > >cases of poisoning? > > > > As Steve points out chelation therapy has a very important and valid use > in the removal of heavy metals from the body. An interesting thought given > the recent study involving the linkage between iron and heart disease > is whether the mechanism of action of EDTA in improving people with > heart conditions might be by binding to and removing iron from the > body. EDTA is known to bind iron and is commonly used for that > purpose in free radical experiments. If it can cause the excretion > of iron (as it does with lead/mercury) then it would have the same > effect as donating blood in lowering ones iron stores. > > Iron has for a number of years been suspected of playing a key role in > free radical generation. [For the chemists, mitochondrial respiration > generates superoxide which is converted by superoxide dismutase to hydrogen > peroxide (H2O2). B-oxidation of fatty acids in the peroxisomes also generates > H2O2. Some fraction of the H2O2 escapes the enzymes catalase and glutathione > peroxidase is converted into hydroxyl radicals which can attack (and oxidize) > DNA, lipids and proteins in a reaction which requires Fe++ or Cu+ ions.] > Since our levels of Fe are much higher than our levels of Cu it is a favorite > choice for involvement in damage to molecules. > > There is a great deal of evidence that oxidized cholesterol is consumed > by macrophages in the process of plaque generation. If the iron-heart > disease link is confirmed then iron would be strongly implicated in > the generation of oxidized cholesterol. If EDTA can reduce iron levels > then it may also reduce oxidized cholesterol levels. This will then > allow gradual cleanup and widening of the arteries to occur as has been > demonstrated in Dean Ornish's work with very low-fat diets. > > Of course this would be relatively easy to test by measuring iron/ferritin/ > transferrin levels of people who undergo chelation therapy. If they drop > significantly after therapy it would be some fairly strong evidence for > the iron-heart disease link as well as interesting support for such therapy > in heart disease treatment. Of course one might be able to obtain the > same effects by frequently donating blood. There is a great epidemiological > study waiting for someone to correlate regular blood donation with heart > disease/cancer rates. > > Robert Bradbury uunet!sftwks!bradbury or rbradbur@u.washington.edu > > It is been a while since I looked at the literature regarding chelation therapy but there used to be a lot of discussion about the problem of iron overload and the use of chelation therapy to treat it. The problem is that people who depend on transfusions, for example in the case of sickle cell anemia and beta thalasemmia build up iron because the body has no way of excreting it. The problem with EDTA was that is was non-specific. That is sufficient quantities to remove iron also chelated things like calcium and magnesium. A fairly specific iron chelator was tried in those days--desferioxamine-- with variable results. Jim Cassatt From owner-ageing@net.bio.net Wed Oct 07 23:00:00 1992 Path: biosci!daresbury!news From: ROUCHDA@VAX1.COMPUTER-CENTRE.BIRMINGHAM.AC.UK (Duncan Rouch) Newsgroups: bionet.molbio.ageing Subject: Copper and Ageing? Message-ID: <1992Oct8.184920.28808@gserv1.dl.ac.uk> Date: 8 Oct 92 19:51:00 GMT Sender: list-admin@daresbury.ac.uk Distribution: bionet Lines: 60 Original-To: AGEING@UK.AC.DARESBURY Hi Netters, I was most interested to see Robert Bradbury's discussion back in August on calorie restriction and slowing of the ageing rate ("Why does calorie restriction reduce the rate of ageing?"). FREE RADICALS AND AGEING? My interest in ageing follows from the potential role of free radical damage to cellular components as part of the ageing process. It is known that metabolic processes generate free radicals. Also, although the radical scavenging mechanisms of the cell are quite efficient, it is likely that they are not 100% effective in preventing radical damage, as Robert discussed. So in going to a a calorie-reduced diet, a lowering of metabolic activity , and or a change to pathway(s) that produces less radicals, might reduce the degree of this damage. TRANSITION METALS AND FREE RADICAL FORMATION: I posit an extension to the view of free radical involvement in ageing, deriving from the interest of our lab in the metabolism of the transition metal copper: that copper might stimulate ageing-related radical formation in vivo. It is well established that copper, and another transition metal, iron, promote the production of free-radicals in vitro. If we assume that damage to cellular DNA is at least partly responsible for the ageing process, then copper is most interesting as it is known in vitro to bind to DNA and cause radical induced damage to it. Some data indicates that this damage induction also occurs in vivo. Co-agents for the copper-induced damage in vitro include metabolic compounds, such as reducing sugars (which help the copper recycle). Cellular systems for handling copper will sequester most of the metal from the potential to cause damage. However, it is tenable that some low level of 'free' copper occurs in cells, due to the affinity of copper for various cell components. So it can be proposed that some of this metal is bound to the DNA. Then, co-agents could act with copper to catalyze radical induced damage to the cellular DNA. These co-agents might be metabolic substrates or products, which are reduced in concentration under a calorie restricted diet. Finally, it is necessary to assume that the DNA repair systems of the cell are not 100% efficient in rebuilding the damaged DNA without error, at least under a non calorie restricted diet. I would be glad of any comments on these ideas about the possible involvement of copper in the ageing process. Duncan Rouch School of Biological Sciences University of Birmingham, U.K. From owner-ageing@net.bio.net Wed Oct 07 23:00:00 1992 Path: biosci!uwm.edu!cs.utexas.edu!sun-barr!ames!elroy.jpl.nasa.gov!sdd.hp.com!nigel.msen.com!emory!ogicse!news.u.washington.edu!hardy.u.washington.edu!rbradbur From: rbradbur@hardy.u.washington.edu (Robert Bradbury) Newsgroups: sci.med.nutrition,bionet.molbio.ageing Subject: Chelation therapy and iron [was Re: Have you heard of this?????] Summary: Is the mechanism of action a reduction in iron load? Message-ID: <1992Oct8.183339.22885@u.washington.edu> Date: 8 Oct 92 18:33:39 GMT References: <1992Oct5.121701.392@lrc.edu> <1992Oct5.170349.19325@spdcc.com> Sender: news@u.washington.edu (USENET News System) Organization: University of Washington, Seattle Lines: 49 Xref: biosci sci.med.nutrition:131 bionet.molbio.ageing:345 In article <1992Oct5.170349.19325@spdcc.com> dyer@spdcc.com (Steve Dyer) writes: >In article <1992Oct5.121701.392@lrc.edu> dorham_r@lrc.edu writes: >>I would like to know if anyone has heard of chelation therapy. If >>anyone has, could you tell me something about it? Thanks!!!! > >Well, there are two kinds of "chelation therapy": are you interested in >the bozoid one that people push to "treat" heart disease, or the legitimate >therapy used to remove heavy metals like lead and mercury from the body in >cases of poisoning? > As Steve points out chelation therapy has a very important and valid use in the removal of heavy metals from the body. An interesting thought given the recent study involving the linkage between iron and heart disease is whether the mechanism of action of EDTA in improving people with heart conditions might be by binding to and removing iron from the body. EDTA is known to bind iron and is commonly used for that purpose in free radical experiments. If it can cause the excretion of iron (as it does with lead/mercury) then it would have the same effect as donating blood in lowering ones iron stores. Iron has for a number of years been suspected of playing a key role in free radical generation. [For the chemists, mitochondrial respiration generates superoxide which is converted by superoxide dismutase to hydrogen peroxide (H2O2). B-oxidation of fatty acids in the peroxisomes also generates H2O2. Some fraction of the H2O2 escapes the enzymes catalase and glutathione peroxidase is converted into hydroxyl radicals which can attack (and oxidize) DNA, lipids and proteins in a reaction which requires Fe++ or Cu+ ions.] Since our levels of Fe are much higher than our levels of Cu it is a favorite choice for involvement in damage to molecules. There is a great deal of evidence that oxidized cholesterol is consumed by macrophages in the process of plaque generation. If the iron-heart disease link is confirmed then iron would be strongly implicated in the generation of oxidized cholesterol. If EDTA can reduce iron levels then it may also reduce oxidized cholesterol levels. This will then allow gradual cleanup and widening of the arteries to occur as has been demonstrated in Dean Ornish's work with very low-fat diets. Of course this would be relatively easy to test by measuring iron/ferritin/ transferrin levels of people who undergo chelation therapy. If they drop significantly after therapy it would be some fairly strong evidence for the iron-heart disease link as well as interesting support for such therapy in heart disease treatment. Of course one might be able to obtain the same effects by frequently donating blood. There is a great epidemiological study waiting for someone to correlate regular blood donation with heart disease/cancer rates. Robert Bradbury uunet!sftwks!bradbury or rbradbur@u.washington.edu From owner-ageing@net.bio.net Wed Oct 14 23:00:00 1992 Path: biosci!parcom.ernet.in!music From: music@parcom.ernet.in (Rajeev Upadhye) Newsgroups: bionet.molbio.ageing Subject: (none) Message-ID: <9210140836.AA02529@parcom> Date: 14 Oct 92 12:46:17 GMT Sender: daemon@net.bio.net Distribution: bionet Lines: 2 subscribe Rajeev Upadhye From owner-ageing@net.bio.net Fri Oct 23 23:00:00 1992 Path: biosci!bcm!cs.utexas.edu!natinst.com!news.dell.com!swrinde!zaphod.mps.ohio-state.edu!wupost!uunet!sftwks!bradbury From: bradbury@sftwks.UUCP (Robert Bradbury) Newsgroups: bionet.molbio.ageing Subject: Re: Copper and Ageing? Summary: Copper and iron -- the jury is out Keywords: copper, iron, ageing Message-ID: <214@sftwks.UUCP> Date: 24 Oct 92 03:04:49 GMT References: <1992Oct8.184920.28808@gserv1.dl.ac.uk> Distribution: bionet Organization: Softworks Ltd, Seattle, WA Lines: 63 In article <1992Oct8.184920.28808@gserv1.dl.ac.uk> ROUCHDA@VAX1.COMPUTER-CENTRE.BIRMINGHAM.AC.UK (Duncan Rouch) writes: > >TRANSITION METALS AND FREE RADICAL FORMATION: > >It is well established that copper, and another transition metal, iron, >promote the production of free-radicals in vitro. > Although Cu does promote free radical formation better than Fe does, the problem is there is 20x as much iron in the body as copper. The best reference on this is: Free Radicals in Biology and Medicine, 2nd Ed B Halliwell, JMC Gutteridge ISBN 0-19-855294-7, Clarendon Press, Oxford 1989 The authors have done a number of experiments in this area over the last 10 years and I think they currently prefer Fe over Cu as a source of damage due to its higher levels in the body. >Cellular systems for handling copper will sequester most of >the metal from the potential to cause damage. However, it is tenable >that some low level of 'free' copper occurs in cells, due to the >affinity of copper for various cell components. So it can be proposed >that some of this metal is bound to the DNA. > Yes, Cu is sequestered by ceruloplasmin among other things. The *really* interesting part is that Fe is normally stored in ferritin as Fe+++; when it is released it must be converted to Fe++. Ceruloplasmin functions as a ferrioxidase since it converts Fe++ to Fe+++ which can be stored back in ferritin. So here you have a case of a protein which protects from oxidative damage from 2 different metals by 2 different methods. What is the probability of this from an evolutionary perspective??? >Then, co-agents could act with copper to catalyze radical induced >damage to the cellular DNA. These co-agents might be metabolic >substrates or products, which are reduced in concentration under >a calorie restricted diet. > Yes, one probably reduces H2O2 formation under CR. It is questionable whether superoxide production is reduced as under CR protein synthesis activities increase and so "in theory" energy requirements go up, as I mentioned before this may be offset by a slight decrease in temperature. >Finally, it is necessary to assume that the DNA repair systems of >the cell are not 100% efficient in rebuilding the damaged DNA >without error, at least under a non calorie restricted diet. > Even when under CR it is still imperfect. > >I would be glad of any comments on these ideas about the >possible involvement of copper in the ageing process. > The experiment waiting to be done is to restrict animals intake of Fe and Cu and determine the relative modification to DNA damage/life-span. Of course given the Fe & Cu both have "good" uses, this approach cuts both ways. Another possibility would be the up-regulation of the ferritin/ceruloplasmin proteins to see if DNA damage is reduced by increasing the probability that the metals will be in stored form rather than drifting around the cell. -- Robert Bradbury uunet!sftwks!bradbury Death is an imposition on the human race, and no longer acceptable Alan Harrington, The Immortalist (1969) From owner-ageing@net.bio.net Fri Oct 23 23:00:00 1992 Path: biosci!news.cs.indiana.edu!sdd.hp.com!cs.utexas.edu!natinst.com!news.dell.com!swrinde!zaphod.mps.ohio-state.edu!wupost!uunet!sftwks!bradbury From: bradbury@sftwks.UUCP (Robert Bradbury) Newsgroups: bionet.molbio.ageing Subject: Evidence against a pre-programmed limit to life span Summary: Science articles provide strong evidence against life span limits Keywords: life-span, ageing Message-ID: <215@sftwks.UUCP> Date: 24 Oct 92 03:37:17 GMT References: <9204211816.AA10577@rust.zso.dec.com> Organization: Softworks Ltd, Seattle, WA Lines: 28 Science (V258:10/16/92) has a comment (p398-99) and two articles (p457-61, 461-63) which provide strong evidence against a programmed limit to life span. Experiments were done on large (1.2 million) medfly cohorts and 4 inbred Drosophila strains and 6 F1 crosses. In both cases they show that the increase in age specific mortality rates levels off or shows large fluctuations in elderly populations. This contradicts the programmed limit theories which predict that age-specific mortality rates should increase continually with age. In my opinion, it also argues quite strongly for genes which are initially neutral or good but later have bad effects leading to death among large fractions of a population (e.g. early onset of maturity leading to increased breast cancer, higher iron intake leading to iron-overload, etc). After these genes have been elimiated from the population, the survivors die off at random rates due to declines in gene/organism function from random mutations. This is not news for those who have read "The Biology of Life Span: Quantitiative Approach" by Drs. Gavrilov and Gavrilova as they have argued that the life table data does not support the idea of life span limits. It may come as a shock however for people who are in the JF Fries camp who are convinced the limit for humans is 85+/-7 years. Ultimately it means that to extend the human life-span we are not working against a program designed by nature but a program which is simply incomplete. -- Robert Bradbury uunet!sftwks!bradbury Death is an imposition on the human race, and no longer acceptable Alan Harrington, The Immortalist (1969) From owner-ageing@net.bio.net Fri Oct 23 23:00:00 1992 Path: biosci!bcm!cs.utexas.edu!usc!sdd.hp.com!uakari.primate.wisc.edu!usenet.coe.montana.edu!news.u.washington.edu!hardy.u.washington.edu!rbradbur From: rbradbur@hardy.u.washington.edu (Robert Bradbury) Newsgroups: sci.med.nutrition,bionet.molbio.ageing Subject: Carcinogen ratings [was Re: Impact of Caffeine on Health] Summary: Caffeine and Caffeic acid are both potential carcinogens Keywords: caffeine, cancer, p53 Message-ID: <1992Oct23.182648.18261@u.washington.edu> Date: 23 Oct 92 18:26:48 GMT References: <1992Oct13.191910.8081@nynexst.com> <45310002@hpgrla.gr.hp.com> Sender: news@u.washington.edu (USENET News System) Followup-To: Distribution: Organization: University of Washington, Seattle Lines: 40 Xref: biosci sci.med.nutrition:357 bionet.molbio.ageing:349 People have commented on caffeine and its effects on migraine headaches and fibrocystic lumps. Caffeine seems to act by interfering with the p53 anti-oncogene gene. The p53 gene is a DNA binding protein which seems to play a key role in delaying cell replication until DNA repair is complete. (See B Vogelstein et al: PNAS 1991 252:1708, Cancer Research 1991 51:6304) Although caffeine may not be a carcinogen itself if it allows cell replication to occur when damaged DNA is present it will increase the mutation rate of cells and increase the probability of getting cancer. That is the bad news. Now, if you look at the article by Bruce Ames in the recent issue of Science (258:261-265) you will discover a ranking of environmental cancer hazards. A quick summary using his "human exposure/rodent potency index" (HERP), a method of comparing hazards using the human exposure level based on the mutagenicity of the substance in rodent tests is: HERP Daily human exposure rodent carcinogen 4.0 wine 250ml alcohol 2.8 beer 12oz alcohol 0.4 home air (14hr/day) formaldehyde 0.3 lettuce (125 g) Caffeic acid 0.1 apple (1) Caffeic acid 0.1 Basil (1g dried leaf) Estragole 0.07 Brown mustard (5g) Allyl isothiocyanate 0.04 Orange juice (6 oz) d-Limonene 0.04 Coffee (1 cup) Caffeic acid 0.005 Coffee (1 cup) Furfural There are a host of other substances in coffee which are carcinogenic as well but all at very small amounts. The key thing in all of this is to realize that there are a large number of substances which are carcinogenic in our diets and our body seems to defend against them fairly well, especially if your intake of anti-carcinogenic agents (Vit C, Vit E, B-carrotene, etc.) is sufficient. However, only about 1 in 10 people get eat the recommended amounts of fruits & vegetables and would obtain recommended levels of these substances naturally. A wise person would assume that consumption of substances which contain harmful chemicals w/o any good chemicals (most alcoholic beverages, coffee, etc.) should be limited. This is especially true of caffeine if at a molecular level it modifies normal gene activity with regard to DNA repair. From owner-ageing@net.bio.net Mon Oct 26 22:00:00 1992 Path: biosci!bcm!cs.utexas.edu!wupost!uunet!sftwks!bradbury From: bradbury@sftwks.UUCP (Robert Bradbury) Newsgroups: sci.med.nutrition,bionet.molbio.ageing Subject: Information distribution [was Re: Protein intake and kidney disease] Summary: There is a gap between the information available and clinical practice Keywords: cholesterol, coenzyme Q, lovostatin/provostatin Message-ID: <216@sftwks.UUCP> Date: 26 Oct 92 09:49:43 GMT References: <1992Oct8.224119.3767@spdcc.com> <1992Oct9.173554.9327@u.washington.edu> <1992Oct13.053710.21608@pegasus.com> Followup-To: sci.med.nutrition Organization: Softworks Ltd, Seattle, WA Lines: 90 Xref: biosci sci.med.nutrition:406 bionet.molbio.ageing:352 In article <1992Oct13.053710.21608@pegasus.com> richard@pegasus.com (Richard Foulk) writes: >In article <1992Oct9.173554.9327@u.washington.edu> I wrote: >>> >>...my comments are rarely based on currently accepted >>medical treatments. They are based on a careful review of the literature >>and some hard thought about what goes on in our bodies as we age. > >Wow. >`Currently accepted medical treatments' used to be based on `careful review >of the literature' and other vehicles of scientific knowledge. >Did that change while I looked away for a minute? > You bet! The problem is that our knowledge base was doubling every 5 years in the early '80's and it doubles faster now. The "bureaucracy" and "inertia" associated with the people who must approve new treatments and lack of time available to the people who must learn and implement them result in a huge delay between our understanding something and it being used to help people. I spend 30-40 hrs/week in class, perusing MEDLINE and reading current journal articles. This is much more time than most doctors or federal bureaucrats have to devote to updating their knowledge base. [There are certainly exceptions to this so please hold the flames.] I have no 'bias' in my research (i.e. no grant to justify, no job to protect, no fear of lawsuits for prescribing "experimental" treatments, etc.). I simply want to understand what we "really" know. Case in point is the lack of awareness among the physicians and the general population about the relationship between cholesterol and coenzyme Q. It has been known since the early '80's that both compounds are derived from the same precursor (HMG-CoA/Mevalonate). There are a large number of people in our society who are on HMG-CoA reductase blockers (provostatin, lovostatin, etc.). The problem with this is that while this lowers cholesterol synthesis it also reduces coenzyme Q synthesis (Ref 1). Given that coenzyme Q occupies a critical path in mitochondrial energy generation and also plays a role protecting lipids from oxidation (Ref 2) one should attempt to maintain or increase coenzyme Q levels. Refs 3&4 show the benifits from doing this. Are medical professionals aware of this? Neither my physician (a young, bright MD from Stanford) nor my pharmacist had any understanding of this. My father's doctor who is prescribing lovostatin for him has not mentioned coenzyme Q. I asked Joseph Goldstein, who won the Nobel prize for the discovery of the cholesterol receptor, about this at the Science Innovation '92 conference in July and he was aware of the relationship but did not offer any explanation as to why other physicians were not. The only conclusion I can draw is that there is a *large* gap between the understanding that the research scientists have and the general distribution of that understanding to most doctors and the general population. Now, I personally find it quite interesting that since I've supplemented my diet with coenzyme Q that my cholesterol level has dropped 10-15 pts. Given the feedback regulation of end-products on precursor synthesis which one commonly finds in biochemical pathways this makes sense. I have yet to find a study which indicates that coenzyme Q supplements can lower cholesterol levels, but in the back of my mind I wonder if the FDA and drug companies are disinclined to publicize/explore this since if it were true it would take a big chunk out of the provostatin/lovostatin market. There is also the interesting 'fact' that in studies where drugs are used to reduce cholesterol there is not a corresponding reduction in the overall mortality rate. Now, if one uses drugs to reduce cholesterol which at the same time reduce coenzyme Q (an antioxidant), then one may increase oxidant levels and the DNA damage associated with them. The result could be a reduction in heart disease with an increase in cancer rates. Thus we trade off diseases whose symptoms we can measure now for those whose consequences are now unknown but which in the end may be identical. I would say that in general "currently accepted medical treatments" are based on literature that is 5-10 years old. Robert Bradbury uunet!sftwks!bradbury Death is an imposition on the human race, and no longer acceptable Alan Harrington, The Immortalist (1969) ----------------------------------------------------------------------- (1) PNAS, 1990, 87:8931-34, K Folkers et al "Lovastatin decreases coenzyme Q levels in humans" (2) PNAS, 1990, 87:4879-83, B Frei, MC Kim, BN Ames "Ubiquinol-10 is an effective lipid-soluble antioxidant..." (3) J. Clin. Pharmacol, 1990, 30:596-608, S Greenberg MD, WH Frishman MD "CoEnzyme Q10: A New Drug for Cardiovascular Disease" (4) Int. J. Tiss. Reac XII(3):163-168, H Per Langsjoen, K Folkers et al "Pronounced Increase of Survival of Patients with Cardiomyopathy When Treated with Coenzyme Q10 and Conventional Therapy"