From owner-ageing@net.bio.net Wed Mar 02 22:00:00 1994 Path: biosci!daresbury!trane.uninett.no!sunic!EU.net!howland.reston.ans.net!europa.eng.gtefsd.com!library.ucla.edu!ihnp4.ucsd.edu!network.ucsd.edu!cmm-mac228.ucsd.edu!user From: obogler@ucsd.edu (Oliver Bogler) Newsgroups: bionet.molbio.ageing Subject: Re: Definition of "Ageing" Followup-To: bionet.molbio.ageing Date: 3 Mar 1994 17:35:38 GMT Organization: Ludwig Inst. for Cancer Res. San Diego Lines: 22 Distribution: world Message-ID: References: <2kd6op$k9s@news.csie.nctu.edu.tw> NNTP-Posting-Host: cmm-mac228.ucsd.edu In article , gobbi@healthy.uwaterloo.ca (gobbi sebastiao) wrote: > > Personally, I like the definition expressed by King (1988) : Aging is > defined as a genetic physiological process associated with morphological > and functional changes in cellular and extracellular components > aggravated by injury troughout life and resulting in a progressive > imbalance of the control regulatory systems of the organism, including > hormonal, autocrine, neuroendocrine and immune homeostatic mechanisms. > > King, D.W. (1988) Pathology and aging. In: Kent, B. & Butler, R. (Eds), > Human Aging Research : concepts and techniques, pp.325 - 340, New York, > NY: Raven Press. But see also C.E. Finch in his book "Longevity, Senescence and the Genome" - he avoids using the term ageing altogether because of it's negative connotation. Instead he discusses age-related changes in a wide variety of organisms - and clearly makes the point that "ageing" is a very different experience for organisms with different life histories. Oliver Bogler obogler@ucsd.edu From owner-ageing@net.bio.net Wed Mar 02 22:00:00 1994 Newsgroups: bionet.molbio.ageing,misc.health.alternative,soc.women Path: biosci!daresbury!trane.uninett.no!sunic!EU.net!howland.reston.ans.net!gatech!swrinde!elroy.jpl.nasa.gov!decwrl!netcomsv!netcom.com!rfoy From: rfoy@netcom.com (Richard Foy) Subject: Free Clinic and Menopausal Women Message-ID: Organization: Netcom - Online Communication Services (408 241-9760 guest) Date: Thu, 3 Mar 1994 20:16:08 GMT Lines: 14 Xref: biosci bionet.molbio.ageing:650 misc.health.alternative:6512 soc.women:27051 This is posted for a friend who works at a Free Clinic. She is preparing a grant request related to post menopausal women. So she asks: What are the medical care requirements of post menopausal women? What are the statistics of the care for these womens, related to medication, doctors treatments etc? Does anyone have any information on this subject or know where on the net, gopher hole, ftp etc, it might be available? -- "A goal is a dream taken seriously" -- Henry David Thoreau rfoy@netcom.com | Richard Foy | Redondo Beach CA From owner-ageing@net.bio.net Mon Mar 07 22:00:00 1994 Path: biosci!sjubiol.stjohns.edu!rick From: rick@sjubiol.stjohns.edu (Richard Lockshin) Newsgroups: bionet.molbio.ageing Subject: reply and query on cell death Date: 8 Mar 1994 04:36:59 -0000 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 82 Sender: daemon@net.bio.net Distribution: bionet Message-ID: <9403072209.AA08098@sjubiol.stjohns.edu> NNTP-Posting-Host: net.bio.net To: ageing@net.bio.net Reply to: uunet!reed.edu!tkim (Tae Hoon Kim) Subject: STUDENT QUESTION: relationship between senescence and apoptosis From: richard a. lockshin -->incidentally, I might as well ask here. Is there much interest in trying to organize a cell death discussion group? ->be careful to distinguish, in the animal world, cell senescence (limited lifespan of cells in culture), programmed cell death (developmental, usually requiring gene activity), and apoptosis (a particular type of morphology and non-lysosomal death seen in many types of cells. -->for aging and cell death, see Lockshin R. A. and Zakeri Z. F., Physiology and protein synthesis in programmed cell death. Early synthesis and DNA degradation. in Franceschi C, Crepaldi G, Cristofalo V. J., and Vijg, J, eds, Aging and Cellular Defense Mechanisms, Annals N.Y. Acad. Sciences 663: 234-249, 1992. 1. Are there evidences that may implicate PKC in the pathwway of cell ageing? -->not that I know of. There are some papers coming out on metabolism of dying cells. 2. Are ultrastructural, morphological, behavior changes in ageing cells similar to apoptotic cells? -->in senescing cells, most people feel that the changes are not like apoptosis. A few feel that they are. Cristofalo is working on this now, and there will be a book out at the end of 94 in which both subjects are treated. My understanding is that dying plant cells do not have the morphology of apoptosis. I solicit references. 3. How is senescence regulated? Or is it regulated at all? -->wow. Do you want a course, a Ph.D., or a Nobel prize? 4. How are ageing cells affected by environment? -->again, senescence: nutrients, glucocorticoids, growth factors play a large role. The environment in general (e.g., ecological concerns) ?? 5. How much evidence are there to suggest that senescence is a genetic process? -->Please see C. Finchs book. Researchers primarily interested in the genetics of senescence include George Martin (U Wash), Tom Johnson (Boulder), Michael Rose (Irvine) 6. What is the relationship between senescence and cell cycle? -->see articles by Judith Campisi, Eugenia Wang, James Smith and Olivia Pereira-Smith, Tom Norwood. You can find these by a literature search. The field is extensive. 7. Can this generalization hold?: Senescence occurs in a terminally differentiated cells, while apoptosis occurs in relatively more neoplastic tissues. -->no. The concepts at present are incommensurable. Interesting thought though. Do you mean instead of neoplastic--a cancerous lesion--mitotic? Can I view apoptosis as a suicide and senescence as a natural death? This distinction seems to helpful in conceptualizing these ideas. -->dont confuse cells and organisms. also, dont confuse continuing mitosis and failure of same with cell death. phase III cells in culture survive a very long time, without undergoing mitosis. Unless you insist on a precise definition of cell senescence, usually considered to refer to limited lifespan of cells in culture, you will end up with total confusion. --richard a. lockshin (rick@sjubiol.stjohns.edu) From owner-ageing@net.bio.net Mon Mar 07 22:00:00 1994 Path: biosci!bcm!cs.utexas.edu!swrinde!gatech!news-feed-1.peachnet.edu!umn.edu!msus1.msus.edu!vax1.mankato.msus.edu!vengeance Newsgroups: bionet.molbio.ageing Subject: Omaha Project Message-ID: <1994Mar8.084413.2357@vax1.mankato.msus.edu> From: vengeance@vax1.mankato.msus.edu Date: 8 Mar 94 08:44:13 -0500 Organization: Mankato State University Lines: 9 I am trying to build a list of names and E-Mail addresses of people in the Omaha Nebraska area for a school related project. If you live in Omaha or go to school there or know someone that does and will be around for three months or more, please reply via E-Mail to Vengeance@vax1.mankato.msus.edu. Thank you very much! Ryan Krueger From owner-ageing@net.bio.net Tue Mar 08 22:00:00 1994 Path: biosci!daresbury!not-for-mail From: Graham Pawelec Newsgroups: bionet.molbio.ageing Subject: EUCAMBIS Date: 9 Mar 1994 14:23:52 -0000 Lines: 66 Sender: daemon@mserv1.dl.ac.uk Distribution: bionet Message-ID: <2lkm5o$bn2@mserv1.dl.ac.uk> Original-To: "bionet discussion group imm. & ageing" , immuno@dl.ac.uk With this posting, allow me to introduce a new initiative of the European Union (EU), scheduled to start at the beginning of April 1994, called EUCAMBIS (= EU Concerted Action on the Molecular Biology of Immunosenescence), of which I am the coordinator. This is one of a large series of EU concerted actions covering many areas of biomedical science. The concept of the concerted action is simply that it should be a mechanism to facilitate the collaboration of different groups (in Europe) on particular areas of research. In our case, we are concentrating on immunosenescence of the T cell, employing an interdisciplinary approach to define genetic events correlating with altered immune functioning in aged individuals. This research network will bring together molecular biologists, gerontologists and immunologists to study T cell function in healthy aged people, patients with progeroid syndromes and other genetic diseases known or suspected to manifest accelerated senescence phenotypes, and to compare these with events occuring in vitro in a long- term culture model of T cell ageing. The expression of growth arrest- specific genes, known tumor-suppressor genes and cell cycle control genes will be investigated in these materials and correlated to cellular immunological function of the cells. We will attempt to isolate novel genes that are upregulated during ageing and to identify senescence- inducing genes or those that contribute actively to the senescent phenotype. Molecular data will be correlated with alterations of function assesssed by cytokine gene transcription and protein secretion, development of cytotoxicity or suppressor capacity. The relationship, if any, between senescence programs and those involved in the special type of T cell growth arrest designated "anergy" will be investigated. Obviously, such a project covers a multitude of sins, and we expect to have to play it by ear. I am particularly keen to hear from non-European scientists interested in any of these areas (but also of course, European workers as well) to start a dialogue on these aspects of immunogerontological research. In an attempt to broaden potential collaboration from its purely European (and small!) base, I am particularly interested to hear from any non-European scientists who might like to work with us for a year or so in Tuebingen (small medieval south-west German University city near Lake Constance, the Alps and the Black Forrest) on this project. We would have to obtain dedicated funding for these persons, but clearly I would assist in the preparation of any applications for funding fellowships, stipendia etc. Please feel free to contact me on the any of the above points, or to request further information on any particular component. With best regards to all readers of this notice, Graham ############################################################ # # # Graham Pawelec, # # Second Department of Internal Medicine, # # University of Tuebingen Medical School, # # D-72076 Tuebingen, Germany; # # # # Coordinator, European Union Concerted # # Action on the Molecular Biology of # # Immunosenescence, EUCAMBIS. # # # # e-mail INTERNET: pawelec@mailserv.zdv.uni-tuebingen.de # # # # Phone: +49-7071-29-2805 # # # # FAX: +49-7071-29-4464 # # # ############################################################ From owner-ageing@net.bio.net Tue Mar 08 22:00:00 1994 Path: biosci!daresbury!trane.uninett.no!nntp.uio.no!hfmac225.uio.no!user From: olava@ilf.uio.no (olav-andreas marschall) Newsgroups: bionet.molbio.ageing Subject: Q10, miracle vitamine slowing down ageing? Followup-To: bionet.molbio.ageing Date: 9 Mar 1994 15:43:49 GMT Organization: univ.of oslo Lines: 6 Distribution: world Message-ID: NNTP-Posting-Host: hfmac225.uio.no I found in recent times several information-guised publicities for a so-called miracle vitamine that presumably slows down ageing by increasing activity level of people at the cell level. Could any wise person help to satisfying my curiosity, is this just another publicity in health-care, or is it really that great and significant ? I would appreciate any comment very much.............. From owner-ageing@net.bio.net Sat Mar 12 22:00:00 1994 Path: biosci!daresbury!trane.uninett.no!sunic!pipex!howland.reston.ans.net!europa.eng.gtefsd.com!news.umbc.edu!haven.umd.edu!cville-srv.wam.umd.edu!theoblit From: theoblit@wam.umd.edu (G-orgasm master) Newsgroups: bionet.molbio.ageing Subject: conferences Date: 12 Mar 1994 16:35:20 GMT Organization: University of Maryland College Park Lines: 9 Message-ID: <2lsr08$2h7@cville-srv.wam.umd.edu> NNTP-Posting-Host: rac5.wam.umd.edu Summary: conferences Keywords: conferences X-Newsreader: TIN [version 1.2 PL0] Dear sirs, Is anyone aware of any upcoming conferences relevant to cellular aging mechanisms? If so, please be kind enough to post here or E-mail me about them. Thanks! From owner-ageing@net.bio.net Sat Mar 12 22:00:00 1994 Newsgroups: bionet.molbio.ageing Path: biosci!agate!howland.reston.ans.net!torn!nott!cunews!freenet.carleton.ca!FreeNet.Carleton.CA!ab341 From: ab341@FreeNet.Carleton.CA (Nadia Diakun-Thibault) Subject: conferences - a partial list Message-ID: Sender: news@freenet.carleton.ca Reply-To: ab341@FreeNet.Carleton.CA (Nadia Diakun-Thibault) Organization: The National Capital FreeNet Date: Sun, 13 Mar 1994 17:43:15 GMT Lines: 15 A partial list of conferences dealing with aging can be found on the National Capital Freenet, Ottawa, Ontario CANADA in a SIG called The Advisory Council on Aging for Lanark, Leeds and Grenville. Telnet freenet.carleton.ca once in at the Your Choice==> prompt type go aging and it will take you directly to the SIG. ### -- Nadia Diakun-Thibault <:> "The greatest use of life is to spend ab341@FreeNet.Carleton.Ca <|> it for something that will outlast it." 3nod@qucdn.queensu.ca <:> William James Alzheimer Society writing contest deadline is March 15th. (613) 722-1424 From owner-ageing@net.bio.net Sat Mar 12 22:00:00 1994 Path: biosci!daresbury!trane.uninett.no!sunic!EU.net!uunet!athos.cc.bellcore.com!gadget9!andrew From: andrew@gadget9.NoSubdomain.NoDomain (Andrew Verba) Newsgroups: bionet.molbio.ageing Subject: idiots Date: 12 Mar 1994 20:05:36 GMT Organization: idiots Lines: 2 Sender: andrew@gadget9 (Andrew Verba) Distribution: world Message-ID: <2lt7ag$jh5@athos.cc.bellcore.com> NNTP-Posting-Host: gadget9.ccs.bellcore.com Keywords: idiots This used to be a serious discussion group. FOOLS! From owner-ageing@net.bio.net Sat Mar 12 22:00:00 1994 Path: biosci!daresbury!not-for-mail From: baret@gena.ucl.ac.be (Ph. Baret) Newsgroups: bionet.molbio.ageing Subject: conferences about genetics of aging ? Date: 12 Mar 1994 18:15:11 -0000 Lines: 13 Sender: daemon@mserv1.dl.ac.uk Distribution: bionet Message-ID: <2lt0rf$n3s@mserv1.dl.ac.uk> X-Sender: baret@sci1.sri.ucl.ac.be Original-To: ageing@dl.ac.uk Dear sirs, In the same spirit as the preceding message, is anyone aware= of any conferences relevant to biology of aging and more specifically to genetics of aging? Thanks! Philippe BARET Unite de Genetique (GENA) - Fac. de Sciences Agronomiques Place Croix-du-Sud 2 bte 14 - 1348 Louvain-la-Neuve (Belgique) t=E9l : 32-10-47.36.71 email : baret @ gena.ucl.ac.be From owner-ageing@net.bio.net Sun Mar 13 22:00:00 1994 Newsgroups: bionet.molbio.ageing Path: biosci!agate!howland.reston.ans.net!pipex!uknet!brunel!md93mgk From: md93mgk@brunel.ac.uk (Michael G Karras) Subject: APOPTOSIS - Programmed cell death (Information needed) Message-ID: Organization: Brunel University, Uxbridge, UK X-Newsreader: TIN [version 1.2 PL2] Date: Mon, 14 Mar 1994 10:50:16 GMT Lines: 18 I'm coming back seeking information on apoptosis aka programmed cell death After seeing this documentary on BBC television I had this very specific query. It was said that cell death comes after stop of communication between similar cells. It was also said that CED-9 gene is responsible for this death. I'm not anexpert on the subject I'm an electronics engineer that has just basic knowledge on life and bio subjects. My query was if that is true how it comes and the egg cell does not need this communication when it's separated by the others. Is there any difference when we talk about egg cells and other cells when apoptosis is concerned? Please I need an answer. It has been troubling me for over than a month and I would like to know more about it. I read a few technical documents but I could not understand anything because it was "too" technical. I would appreciate if anybody could forward this message to anybody who could give me an answer. I am desperate about it. Thank you very much in advance Michael Karras From owner-ageing@net.bio.net Sun Mar 13 22:00:00 1994 Path: biosci!daresbury!not-for-mail From: Graham Pawelec Newsgroups: bionet.molbio.ageing Subject: T cell senescence project "EUCAMBIS" Date: 14 Mar 1994 17:29:08 -0000 Lines: 66 Sender: daemon@mserv1.dl.ac.uk Distribution: bionet Message-ID: <2m26t4$9sg@mserv1.dl.ac.uk> Original-To: "bionet discussion group imm. & ageing" , immuno@dl.ac.uk With this posting, allow me to introduce a new initiative of the European Union (EU), scheduled to start at the beginning of April 1994, called EUCAMBIS (= EU Concerted Action on the Molecular Biology of Immunosenescence), of which I am the coordinator. This is one of a large series of EU concerted actions covering many areas of biomedical science. The concept of the concerted action is simply that it should be a mechanism to facilitate the collaboration of different groups (in Europe) on particular areas of research. In our case, we are concentrating on immunosenescence of the T cell, employing an interdisciplinary approach to define genetic events correlating with altered immune functioning in aged individuals. This research network will bring together molecular biologists, gerontologists and immunologists to study T cell function in healthy aged people, patients with progeroid syndromes and other genetic diseases known or suspected to manifest accelerated senescence phenotypes, and to compare these with events occuring in vitro in a long- term culture model of T cell ageing. The expression of growth arrest- specific genes, known tumor-suppressor genes and cell cycle control genes will be investigated in these materials and correlated to cellular immunological function of the cells. We will attempt to isolate novel genes that are upregulated during ageing and to identify senescence- inducing genes or those that contribute actively to the senescent phenotype. Molecular data will be correlated with alterations of function assesssed by cytokine gene transcription and protein secretion, development of cytotoxicity or suppressor capacity. The relationship, if any, between senescence programs and those involved in the special type of T cell growth arrest designated "anergy" will be investigated. Obviously, such a project covers a multitude of sins, and we expect to have to play it by ear. I am particularly keen to hear from non-European scientists interested in any of these areas (but also of course, European workers as well) to start a dialogue on these aspects of immunogerontological research. In an attempt to broaden potential collaboration from its purely European (and small!) base, I am particularly interested to hear from any non-European scientists who might like to work with us for a year or so in Tuebingen (small medieval south-west German University city near Lake Constance, the Alps and the Black Forrest) on this project. We would have to obtain dedicated funding for these persons, but clearly I would assist in the preparation of any applications for funding fellowships, stipendia etc. Please feel free to contact me on the any of the above points, or to request further information on any particular component. With best regards to all readers of this notice, Graham ############################################################ # # # Graham Pawelec, # # Second Department of Internal Medicine, # # University of Tuebingen Medical School, # # D-72076 Tuebingen, Germany; # # # # Coordinator, European Union Concerted # # Action on the Molecular Biology of # # Immunosenescence, EUCAMBIS. # # # # e-mail INTERNET: pawelec@mailserv.zdv.uni-tuebingen.de # # # # Phone: +49-7071-29-2805 # # # # FAX: +49-7071-29-4464 # # # ############################################################ From owner-ageing@net.bio.net Sun Mar 13 22:00:00 1994 Path: biosci!daresbury!not-for-mail From: Kurt Schaudt Newsgroups: bionet.molbio.ageing Subject: Re.: APOPTOSIS - Programmed cell death (Information needed) Date: 14 Mar 1994 20:13:14 -0000 Lines: 127 Sender: daemon@mserv1.dl.ac.uk Distribution: bionet Message-ID: <2m2ggq$hie@mserv1.dl.ac.uk> Original-To: Ageing discussion group >This section is from the document '/AGEING/current'. > >From BIOSCI-REQUEST Mon Mar 14 11:40:15 1994 >Received: from localhost by net.bio.net (8.6.5/IG-2.0) > id LAA03021; Mon, 14 Mar 1994 11:40:15 GMT >Received: from localhost by net.bio.net (8.6.5/IG-2.0) > id DAA03017; Mon, 14 Mar 1994 03:40:13 -0800 >To: ageing >From: md93mgk@brunel.ac.uk (Michael G Karras) >Subject: APOPTOSIS - Programmed cell death (Information needed) >Message-ID: >X-Newsreader: TIN [version 1.2 PL2] >Date: Mon, 14 Mar 1994 10:50:16 GMT > >I'm coming back seeking information on apoptosis aka programmed cell death >After seeing this documentary on BBC television I had this very specific >query. It was said that cell death comes after stop of communication >between similar cells. It was also said that CED-9 gene is responsible >for this death. I'm not anexpert on the subject I'm an electronics >engineer that has just basic knowledge on life and bio subjects. >My query was if that is true how it comes and the egg cell does not need >this communication when it's separated by the others. Is there any >difference >when we talk about egg cells and other cells when apoptosis is concerned? >Please I need an answer. It has been troubling me for over than a month >and I would like to know more about it. I read a few technical documents >but I could not understand anything because it was "too" technical. >I would appreciate if anybody could forward this message to anybody who >could give me an answer. I am desperate about it. >Thank you very much in advance > >Michael Karras Dear Michael, Consider that apoptosis is mediated by signalling events within the cell. Cell surface receptors (peptides or proteins fixed on the cell membran, capable of binding other peptides), like the APO1 - receptor (capable of mediating apoptosis), interact with most specific suitable other substances (eg. peptides), resulting in a particular intracellular signal. This signal may induce apoptosis (eg. by enhancing calcium influx and so activating the endonucleases) or may prevent the cell from it (eg. by downregulating apoptotic signals), depending on the kind of the receptor. Expression of these receptors depends on the genetic program the cell is processing - this program depends on the kind of differentiation of the cell and on its state of differentiation. Apoptosis anyway is a process of strongly making sense. If a cell differenciated to be a member of a particular tissue with a special function escapes to another tissue, it is not desirable that this cell will overcome and even divide. So this cell will express a special kind of receptor (called adhesion molecule) which will bind to another receptor molecule (same type) of a cell of the same type and both of this receptors will hinder the other to produce an apoptotic signal. Within the particular tissue most of these adhesion molecules are bound to a suitable other of the neighbourhood cell and so apoptosis is prevented. If such a cell escapes from the tissue and looses contact to the appropriate cells, the now "free" receptor molecules will mediate an apoptotic signal event (or they will stop antiapoptotic signal events). The special kind of such receptors (adhesion molecules) depend strongly on the differentiation status of the cell. So eg. liver cells only will express receptors specific for liver cells, if they escape eg. to the stomach, they will lack their appropriate partner molecules and so undergo apoptosis. Another example for apoptosis is the immune system. Its apoptotic events are special cases of the "common apoptosis". For they lack tissue like cell - cell contact their "communication" is mediated by so called "interleukines" (water soluble peptides in the blood and the tissue fluids). Here apoptosis is necessary because at the beginning of an infection suitable cells are expanded in greatest extend (by deviding) to overcome the infection quickly, at the end of the infection however these (exponential !) cellular growth events must be extinguished very quickly and carefully to prevent uncontrolled growth of cells (as seen in leucaemic diseases). Growth of this kind of cells is mediated by these interleukins which's signalling events prevent the cell from apoptosis. Note: these cells of the immune system dont need direct cell - cell contact for not to undergo apoptosis. The reason for this is the lack of molecules on the cell surface which need direct cell - cell contact for preventing apoptosis (but they are replaced in function by the interleukin receptors). That doesn't say that immune cells have no adhesion molecules at all but in immune cells they have different functions (due to other molecules on the cell's surface). This is underlining the fact that the cell has greatest flexibility to alter its nature by expression particular molecules (on the cell surface) or not, governed by its special state of differentiaton. This remarks should help you to explain your question: If the differentiation state of an egg cell is a genetic program which doesn't at all express receptors capable for mediating apoptosis it cannot undergo apoptosis. You haven't mentioned which kind of egg cells you meaned especially, but this is true for all kinds: if you meaned for example fish eggs, they after spawning lack cell - cell contact and so their genetic program after maturing will not express apoptotic mediating receptor molecules at all. if you meaned eg. human eggs they of course will express receptor molecules specific for the tissues they are surrounded with in the normal case which prevents them from dividing in abnormal surroundings. But note: apoptosis is not governed alone by those apoptotic signal events but also by expression of other gene products: the endonucleases themselfes (which mediates apoptosis by cleaving the cellular DNA into small and useless fractions), suppressors of these endonucleases, suppressors of their action on the DNA and so on ... Hope this helps a little ! (And, as a natural scientist, I hope that answering this one question will arise a couple of new others - as usual in this kind of science. By the way, I appreciate interest of non specialists in these things because their (at first sight simple to answer) questions in praxi proove to be answered not quite so simple than expected and, maybe, they may be able to give worthy contributions from their fields and their points of view. Especially specialists in electronics may recognize phenomena in control, regulation and biological "control engineering" earlier than "only" specialists in biology do, so I want to encourage all people (even non biologists) with interest in those phenomena to enter such discussions.) Kurt Schaudt, kschaudt@mailserv.zdv.uni-tuebingen.de Medical School of Tuebingen From owner-ageing@net.bio.net Mon Mar 14 22:00:00 1994 Path: biosci!sjubiol.stjohns.edu!rick From: rick@sjubiol.stjohns.edu (Richard Lockshin) Newsgroups: bionet.molbio.ageing Subject: Apoptosis - programmed cell deth (information needed) reply Date: 15 Mar 1994 05:53:35 -0000 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 40 Sender: daemon@net.bio.net Distribution: bionet Message-ID: <9403141805.AA10662@sjubiol.stjohns.edu> NNTP-Posting-Host: net.bio.net To: ageing@net.bio.net From: rick@sjubiol.stjohns.edu (Richard A. Lockshin) Subject: APOPTOSIS - Programmed cell death (Information needed)--reply Answers to: uunet!brunel.ac.uk!md93mgk (Michael G Karras) 1. Apoptosis is a specific morphology in the general category of physiological cell deaths. It includes movement of the chromatin to the margin of the nucleus, coalescence of the chromatin, usually but not always degradation of the DNA to characteristic small fragments termed a nucleosomal ladder, and shrinkage and fragmentation of the cell. If one can further establish that the cell follows a specific sequence to its death, including synthesis of new messages and proteins, the death is called programmed. The terms are frequently interchanged, though they are slightly different. You may wish to consult "Apoptosis. The Molecular Basis of Cell Death", edited by L. D. Tomei and F. O. Cope, Cold Spring Harbor Laboratory Press, 1991, or several lead articles in Cell Biology International for 1993, notably those by Bowen and his colleagues. Both of these should be available to you. 2. Dead cells have severed their connections with other cells, but the causal and temporal connections between severing and death are not known. Ced-9 is a gene that in the nematode Caenorhabditis elegans prevents known programmed deaths. It is slightly similar to a mammalian gene, bcl-2, but it has not been identified elsewhere. It is a gene of enormous interest. There was a review in Annual Reviews of Cell Biology in, I believe, 1991, by (Ellis and?) H. R. Horvitz on this subject. 3. We (workers in the field) tend to feel that most cells are capable of killing themselves (programmed cell death or apoptosis), including probably unfertilized eggs. A lot of work is going into the question, because it has many ramifications in cancer, aging, neurobiology, and immunology including AIDS. There are a few thousand publications now, with the number increasing logarithmically. Stay tuned. 4. Obviously, as you correctly observed, many cells, including blood cells and eggs, do not need to maintain cell-to-cell contact and in fact abandon it. Given the proper nutritional background, most cells can survive, albeit wanly, out of contact with others. (The dependent clause there is a big "if".) From owner-ageing@net.bio.net Mon Mar 14 22:00:00 1994 Path: biosci!bcm!mbcr.bcm.tmc.edu!th035681 From: th035681@mbcr.bcm.tmc.edu (Timothy R. Hughes) Newsgroups: bionet.molbio.ageing Subject: re: aging FAQ Date: 15 Mar 1994 18:41:19 GMT Organization: Baylor College of Medicine, Houston, Tx Lines: 26 Distribution: world Message-ID: <2m4vgf$fqb@gazette.bcm.tmc.edu> NNTP-Posting-Host: mbcr.bcm.tmc.edu I am working on a FAQ for this newsgroup that I hope to post around the beginning of April. I am looking for the following references - could nyone help me? I have access to medline and a large medical research library, but I can't seem to dig up the following: 1.) Statistics on cuase of death for the U.S. as a whole and for, say, persons over 60. 2.) easily interpreted health statistics for the aging in general. (I have been advised to consult actuarial tables for the above but I don't have time.) 3.) a simple list of medical "biomarkers of aging", not related to death or disease 4.) A complete listing of the various progeroid syndromes ranked by phenotype and age of onset. Any help is appreciated. Thanks, -- Tim Hughes From owner-ageing@net.bio.net Wed Mar 16 22:00:00 1994 Path: biosci!CS.Arizona.EDU!math.arizona.edu!news.Arizona.EDU!hamblin.math.byu.edu!news.byu.edu!gatech!howland.reston.ans.net!europa.eng.gtefsd.com!emory!swrinde!menudo.uh.edu!oac4.hsc.uth.tmc.edu!oac4.hsc.uth.tmc.edu!ylek From: ylek@utmdacc.uth.tmc.edu (David Voehringer) Newsgroups: bionet.molbio.ageing Subject: Apoptosis and Programmed Cell Death (PCD) Date: Thu, 17 Mar 1994 11:49:26 Organization: UTMDACC Lines: 3 Message-ID: NNTP-Posting-Host: drad55.mda.uth.tmc.edu Keywords: Cell Death, apoptosis X-Newsreader: Trumpet for Windows [Version 1.0 Rev A] I saw a post a few days back suggesting the formation of an Apoptosis group. I would also be interested in this since the research we are doing right now focuses on apoptosis. How does a new group get formed? From owner-ageing@net.bio.net Thu Mar 17 22:00:00 1994 Path: biosci!daresbury!trane.uninett.no!eunet.no!EU.net!howland.reston.ans.net!europa.eng.gtefsd.com!news.umbc.edu!haven.umd.edu!cville-srv.wam.umd.edu!theoblit From: theoblit@wam.umd.edu (G-orgasm master) Newsgroups: bionet.molbio.ageing Subject: Re: Apoptosis and Programmed Cell Death (PCD) Date: 18 Mar 1994 13:45:39 GMT Organization: University of Maryland College Park Lines: 13 Message-ID: <2mcba3$hsa@cville-srv.wam.umd.edu> References: NNTP-Posting-Host: public-35.circa.ufl.edu The Christian Bible never work because it is not from God. In article , acarpent@osprey.ess.harris.com (Alan Carpenter) wrote (according to the christian Bible): > 1. Homosexuality is considered to be a sin in the Bible. It is given > as being no better or worse than other sexual sins What is the big deal? All other countries, except the U.S.A. considered Homosexuality is crime. Most countries, except the U.S.A. considered other sexual sins as crime. What do you try to prove, tough on "CRIME" (depend on who is the judge)? Is it a "CRIME" to eat DOG meat, too? What Bible? Which visions are you talking about? You don't have ONLY ONE book! You don't have a Bible! Does God speak your language? Bible is not in english and Jesus is not white. > 2. Sin in general drives a wedge between the sinner and God. > Sexual sins, however, are called out for especially harse judgement How harse your judgement can be? Both Russia and the old Soviet Union ban Homosexuality. Gays were jailed during Stalin time. Sexual criminals were punished with death. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ A lot of Christians believed that the earth is a living hell. The truth is that most non-Christians enjoy life more in this "living hell". How harse the judgement of Christians can be? Tell us how bad another "hell" is. Most Christians wanted to live longer, right? They spent a lot of money to make themself heathy because they tried to avoid "heaven". > 3. Shall we continue in sin, that grace [for the saved] may abound? > That's the question Paul asks. The clear answer is NO. The fact is that everything is against your will now. Everything is against the Bible. You can not do anything. Nothing! Do you get it! Take you wound and forget about your religion!!! > 4.Sin is not part of our nature as Christians (for > those truly saved). Why more christians raped their won children in the Christian Nation? Why more christians went to topless bars in the Christian Nation? Why the Christian Nation builded more topless bars than any other non-christian nations? > Paul himself told the church not to judge those outside of it, > only those who call themselves believers. Sure, Paul know who is the true sinners! Beside, it depends on what kind of judgement you are talking about. The typical judgement of the church is that "God forgvie you, you can sin again in the very next day" > [Christ Himself judged the religious leaders the harshest since > they were the ones charged with upholding the truth!] Are you sure about that? "Sinners" are usually happier than anyone else in the Christian Nation. Religious leaders usually love to kiss their ass. > I am NOT anti-gay for the sake of the argument: I am anti-sin, > but not anti-sinner. > -- Alan I am NOT anti-christian for the hell of debate: I am anti-christianity, but not anti-christian. --- Believe it or not. It is only a joke! Don't burn a cross in front of my house because I am NOT anti-christian. > | "CONCENSUS IS THE DEATH OF LEADERSHIP" -- Lady Margaret Thatcher | > | ALAN W. CARPENTER HARRIS CORPORATION, INFORMATION SYSTEMS DIV | > | acarpent@dw3f.ess.harris.com MELBOURNE, FLORIDA 32902 | Do you have any concensus at all? If you do, I would let you to choose between Soul and Life. What Lady Margaret Thatcher think about male stipper? From owner-ageing@net.bio.net Thu Mar 17 22:00:00 1994 Newsgroups: bionet.molbio.ageing Path: biosci!daresbury!trane.uninett.no!eunet.no!EU.net!howland.reston.ans.net!europa.eng.gtefsd.com!news.umbc.edu!haven.umd.edu!purdue!mozo.cc.purdue.edu!vet.vet.purdue.edu!narayana From: narayana@vet.vet.purdue.edu (Padmakumar Narayanan) Subject: Apoptosis and glutathione Sender: news@mozo.cc.purdue.edu (USENET News) Message-ID: Date: Fri, 18 Mar 1994 20:39:01 GMT Organization: Purdue University SVM Lines: 13 Dear nettors, I recently came across articles in NATURE and CELL that stated that a decreased glutathione level and an increased lipid peroxidation activity was associated with apoptosis in thymocytes. They also stated that the increased lipid peroxidation was not associated with the NADPH Oxidase complex in the plasma membrane. Can an increased mitochondrial respiratory activity lead to this phenomenon. Any thoughts about it? Padma kumar narayanan purdue cytometry labs purdue university w. lafayette in From owner-ageing@net.bio.net Thu Mar 17 22:00:00 1994 Path: biosci!DRUID.HSC.COLORADO.EDU!mandy From: mandy@DRUID.HSC.COLORADO.EDU (Mandy Caird PhD) Newsgroups: bionet.molbio.ageing Subject: Re: Sexual Sin and Christian Date: 18 Mar 1994 13:23:15 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 32 Sender: daemon@net.bio.net Distribution: bionet Message-ID: References: NNTP-Posting-Host: net.bio.net On Fri, 18 Mar 1994, Christian Sin wrote: > The Christian Bible never work because it is not from God. > > In article , acarpent@osprey.ess.harris.com > (Alan Carpenter) > wrote (according to the christian Bible): > > > 1. Homosexuality is considered to be a sin in the Bible. It is given > > as being no better or worse than other sexual sins > > What is the big deal? All other countries, except the U.S.A. considered > Homosexuality is crime. Hang-on a minute, am I on the aging net? What is dribble like this doing on what I thought was a Biological Science net, for Human Biologists, etc. First, homosexuality in not a sin in many more countries than the USA, and I hope in the minds of most of the people who read this net. And secondly, I thought there was an overwhelming belief in the Scientific community that homosexuality will eventually be proved to be genetically linked (probably through something on the the X chromosome!). What has the Bible got to do with molecular biology and genetics? They are two VERY different subjects that both deserve respect, but should NEVER be linked together in a discussion (there are too many contradictions) especially around scientists who generally want some kind of physical proof. All you homophobes should try reading the women in science net. Sexuality is discussed, but it is never classed "a sin". Mandy From owner-ageing@net.bio.net Sat Mar 19 22:00:00 1994 Path: biosci!daresbury!trane.uninett.no!sunic!pipex!howland.reston.ans.net!vixen.cso.uiuc.edu!news.uoregon.edu!netnews.nwnet.net!news.u.washington.edu!rbradbur From: rbradbur@u.washington.edu (Robert Bradbury) Newsgroups: bionet.molbio.ageing Subject: Re: Apoptosis and glutathione Date: 20 Mar 1994 01:41:29 GMT Organization: University of Washington, Seattle Lines: 48 Sender: bradbury@aeiveos.wa.com Message-ID: <2mg9k9$ork@news.u.washington.edu> References: NNTP-Posting-Host: hardy.u.washington.edu Summary: Reduced glutathione levels may lead to DNA damage and apoptosis In article , Padmakumar Narayanan wrote: > >I recently came across articles in NATURE and CELL that stated that a decreased >glutathione level and an increased lipid peroxidation activity was associated >with apoptosis in thymocytes. >Can an increased mitochondrial respiratory activity lead to this phenomenon. >Any thoughts about it? > Glutathione is one of the major cellular defenses against free radicals and since mitochondrial respiration is one of the major pathways producing free radicals high levels of activity lead to glutathione depletion. This will result in lipid peroxidation and can be measured in animals/humans after high levels of exercise as exhaled pentane gas. You don't indicate how the experimentors depleted the glutathone. Usually this can be done by exposing cells to oxidizing agents or xenobiotics which use up the available glutathione. Sometimes agents which block glutathione synthesis are used as well. At any rate the high concentrations of glutathione in cells it serves as a major target for free radicals. If the glutathione levels are depleted the free radicals will damage the lipids, proteins and DNA. One of the functions of the p53 gene seems to involve detecting high levels of DNA damage (potentially unrepairable) and trigger an apoptosis(-like?) response. This makes sense from an evolutionary standpoint since cells with high levels of DNA damage are potentially pre-cancerous so in tissues with replacement capacity (liver, immune system, skin, etc.) it would be better to have them commit suicide rather than risk cancer. Unfortunately in other tissues (brain, muscle, etc.) the cells are not replaced and you have a decline in function. I was at a conference last year in which they measured levels of glutathione in various parts of the brain. Glutathione is synthesized by the liver using sulfur-containing amino acids in your food (cysteine/ methionine). The glutathione is then exported from the liver for use by various tissues with less synthesis capacity. In the parts of the brain with high activity or production of damaging agents (e.g. H2O2 production during dopamine synthesis in the S. nigra) there is a rapid decline in glutathione levels within 3-4 hours after a meal. This decline probably increases the risk of cell death for cells in those brain areas. So if one wants to live a long life with reduced risk of Parkinsons/ Alzheimers then one probably wants to eat small frequent meals which have a fairly high sulfur content (e.g. garlic) and/or supplement with glutathione/cysteine in an easily absorbed form (probably N-acetyl cysteine). Robert Bradbury bradbury@aeiveos.wa.com From owner-ageing@net.bio.net Sat Mar 19 22:00:00 1994 Path: biosci!sjubiol.stjohns.edu!rick From: rick@sjubiol.stjohns.edu (Richard Lockshin) Newsgroups: bionet.molbio.ageing Subject: apoptosis and programmed cell death Date: 19 Mar 1994 21:54:01 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 26 Sender: daemon@net.bio.net Distribution: bionet Message-ID: <9403191551.AA12673@sjubiol.stjohns.edu> NNTP-Posting-Host: net.bio.net To: ageing@net.bio.net Subject: Re: Apoptosis and Programmed Cell Death (PCD) From: uunet!wam.umd.edu!theoblit (G-orgasm master) replied to: David Voehringer (ylek@utmdacc.uth.tmc.edu) wrote: : I saw a post a few days back suggesting the formation of an Apoptosis group. : I would also be interested in this since the research we are doing right now : focuses on apoptosis. How does a new group get formed? : In regards to splitting this newgroup in to one for general :aging and just apoptosis I would like to point out a few things. This :newgroup is already so small as to be on weak foundations. To split :it up even more would make the situation worse. Secondly, I already :have to search two newgroups for information on aging. If this is :split, that will make it three. I personally would like to keep this :newsgroup as it is. I sympathize with the problems related above, and currently there is some discussion of apoptosis in aging. However, the subject more generally belongs to the cell biology group. I am interested in counting noses as to how many are interested in seeing apoptosis discussions in cell biology and how many are interested in seeing them in aging. --richard lockshin rick@sjubiol.stjohns.edu From owner-ageing@net.bio.net Sat Mar 19 22:00:00 1994 Path: biosci!bcm!cs.utexas.edu!swrinde!sgiblab!sgigate.sgi.com!olivea!news.bu.edu!noc.near.net!news.delphi.com!usenet From: proctorp@delphi.com Newsgroups: bionet.molbio.ageing Subject: Re: re: aging FAQ Date: Sun, 20 Mar 94 11:24:57 -0500 Organization: Delphi (info@delphi.com email, 800-695-4005 voice) Lines: 25 Message-ID: References: <2m4vgf$fqb@gazette.bcm.tmc.edu> NNTP-Posting-Host: bos1f.delphi.com X-To: Timothy R. Hughes Re: Some Markers of Aging 1) Inspiratory capacity ( measures lung and chest compliance ) 2) Age need bifocals ( measures lens aging ) 3) Age of appearance of pattern hair loss. In males, the incidence of pattern loss roughly corresponds to age-- e.g. at age 35 about 35% of males shown pattern loss. Possibly because of increased mortality of severely balding males, this correlation does not hold after age 70 ( Ref: Klingman, Clinics in Dermatology, Oct-Dec. 1988 ) 4) Other skin markers include appearance of facial lines. However, this is confounded by Light exposure and facial expression habits. Rough time of appearance of lines: Forehead and glabellar lines: early '30's Lower quadrant " crows feet ": mid '30's Upper quadrant " crows feet " Late '30's, early '40's Peter H. Proctor, PhD,MD Suite 1616, 4126 SW Freeway Houston, TX 77027 (713) 960-1616 From owner-ageing@net.bio.net Sun Mar 20 22:00:00 1994 Path: biosci!bcm!mbcr.bcm.tmc.edu!th035681 From: th035681@mbcr.bcm.tmc.edu (Timothy R. Hughes) Newsgroups: bionet.molbio.ageing Subject: Re: apoptosis and programmed cell death Date: 21 Mar 1994 03:04:35 GMT Organization: Baylor College of Medicine, Houston, Tx Lines: 10 Distribution: bionet Message-ID: <2mj2s3$21h@gazette.bcm.tmc.edu> References: <9403191551.AA12673@sjubiol.stjohns.edu> NNTP-Posting-Host: mbcr.bcm.tmc.edu Here's my two cents - I think it's OK to discuss apoptosis. I don't believe it's been proven that apoptosis is _not_ involved in aging, and I think this discussion is probably clearing up the difference between apoptosis and cell senescence. Furthermore, it is now evident that a lot more people are reading this newsgroup than I thought! -- Tim Hughes From owner-ageing@net.bio.net Sun Mar 20 22:00:00 1994 Path: biosci!NVEGW.CRL.AECL.CA!Clive.L.Greenstock From: Clive.L.Greenstock@NVEGW.CRL.AECL.CA Newsgroups: bionet.molbio.ageing Subject: mitochondria Date: 21 Mar 1994 12:04:21 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 5 Sender: daemon@net.bio.net Distribution: bionet Message-ID: <940321145126751-MTANVE*Clive.L.Greenstock@NVE.CRL.AECL.CA> NNTP-Posting-Host: net.bio.net Can anyone tell me how many mitochondria there are in human lymphocytes and fibroblasts (references please0. Clive Greenstock AECL Research Chalk River Canada greenstockc@NVE.CRL.AECL.CA From owner-ageing@net.bio.net Sun Mar 20 22:00:00 1994 Path: biosci!ESSEX.HSC.COLORADO.EDU!santhosc From: santhosc@ESSEX.HSC.COLORADO.EDU (Santhosh) Newsgroups: bionet.molbio.ageing Subject: apoptosis/sin/bible Date: 21 Mar 1994 10:49:02 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 3 Sender: daemon@net.bio.net Distribution: bionet Message-ID: Reply-To: Santhosh NNTP-Posting-Host: net.bio.net I guess its better to discuss apoptosis in this group than discuss sin/bible/homosexuality ete. Why is religion discussed in this group anyway? From owner-ageing@net.bio.net Sun Mar 20 22:00:00 1994 Path: biosci!daresbury!trane.uninett.no!eunet.no!EU.net!howland.reston.ans.net!noc.near.net!news.delphi.com!usenet From: proctorp@delphi.com Newsgroups: bionet.molbio.ageing Subject: Re: Sexual Sin and Christian Date: Sun, 20 Mar 94 22:17:59 -0500 Organization: Delphi (info@delphi.com email, 800-695-4005 voice) Lines: 3 Message-ID: References: NNTP-Posting-Host: bos1a.delphi.com X-To: Mandy Caird PhD The section in Leviticus which calls homosexuality an abomination also calls touching pigskin an abomination. No more football or gloves for me then ! From owner-ageing@net.bio.net Sun Mar 20 22:00:00 1994 Path: biosci!MIRANDA.UMDS.AC.UK!fsymons From: fsymons@MIRANDA.UMDS.AC.UK (Fernley Symons) Newsgroups: bionet.molbio.ageing Subject: (none) Date: 21 Mar 1994 12:19:31 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 1 Sender: daemon@net.bio.net Distribution: bionet Message-ID: <2521.9403212002@miranda.umds.ac.uk> NNTP-Posting-Host: net.bio.net unsubscribe From owner-ageing@net.bio.net Mon Mar 21 22:00:00 1994 Path: biosci!daresbury!trane.uninett.no!sunic!pipex!howland.reston.ans.net!europa.eng.gtefsd.com!news.uoregon.edu!netnews.nwnet.net!news.u.washington.edu!rbradbur From: rbradbur@u.washington.edu (Robert Bradbury) Newsgroups: bionet.molbio.ageing Subject: Re: apoptosis and programmed cell death Date: 22 Mar 1994 09:02:14 GMT Organization: University of Washington, Seattle Lines: 35 Distribution: bionet Message-ID: <2mmc6m$hg7@news.u.washington.edu> References: <9403191551.AA12673@sjubiol.stjohns.edu> <2mj2s3$21h@gazette.bcm.tmc.edu> NNTP-Posting-Host: hardy.u.washington.edu Summary: Apoptosis may both prevent and cause aging In article <2mj2s3$21h@gazette.bcm.tmc.edu>, Timothy R. Hughes wrote: > -- makes a point that apoptosis may be involved in aging > and may or may not be related to cell senescence It is clear that the normal use of apoptosis is for developmental purposes. This pathway may have been "adopted" by the evolutionary mechanisms which extend lifespan by removing severely damaged [potential harmful (pre-cancerous) cells]. The p53 gene is involved in the detection of excessive DNA damage and may trigger an apoptosis(-like) process. This is "good" for the prevention of cancer and "bad" for the overall longevity of the organism as the loss of cells which are not replaced leads to a long-term decline of function ("aging"). The cell-senescence process (loss of the ability to divide) may be related to the shrinkage of the telomeres on the ends of the chromosomes with each cell division. This may be a "fail-safe" mechanism since DNA-polymerase has a relatively fixed error rate in copying DNA and after a certain number of copies a number of potentially cancer causing mutations may have been reproduced in the genome. So better to prevent cell division (senescence) than allow the number of mutated cells to increase. The big question is whether senescence is due to a direct effect of telomere-shortening or by a more indirect effect involving detection of DNA damage by p53(-related mechanisms) causing an extended block of cell division. Things to consider in this when thinking about this are: a) Rodents have longer telomeres and higher cancer rates than humans. These may be related since longer telomeres would allow more cell divisions (= more mutations) before cell sensencence was activated. These may be unrelated since humans seem to have an extra "block" on cell division which may be triggered by detecting DNA damage. b) Cells from premature aging syndrome patients (Werner's Syndrome) have a reduced division potential (earlier senescence). They is some evidence which suggests they are defective in one or more critical DNA repair enzymes. Robert Bradbury bradbury@aeiveos.wa.com From owner-ageing@net.bio.net Mon Mar 21 22:00:00 1994 Path: biosci!bcm!mbcr.bcm.tmc.edu!th035681 From: th035681@mbcr.bcm.tmc.edu (Timothy R. Hughes) Newsgroups: bionet.molbio.ageing Subject: DNA damage paradoxes Date: 22 Mar 1994 19:24:17 GMT Organization: Baylor College of Medicine, Houston, Tx Lines: 24 Distribution: world Message-ID: <2mngl1$13u@gazette.bcm.tmc.edu> NNTP-Posting-Host: mbcr.bcm.tmc.edu I am about curious about a couple of things: 1) If any kind of universal, irreversible cellular damage (to proteins, DNA, lipids, cell structure, whatever) is responsible for aging, then how is it that the germ line cells manage to escape this and go on to make a new organism with a reset "biological clock"? Deleterious mutations do not seem to arise with overwhelming frequency, as evidenced by the ability of some women to have ten or twelve healthy children. The germ cells must undergo oxidative phosphorylation, or they will die from inability to maintain membrane gradients if nothing else. If there's a selection scheme for the best eggs and sperm, how would it work for genes which aren't expressed - for example, liver, muscle, and CNS-specific genes, which between the three represent probably more than half the genome? Is there something magical about meiosis or fertilization? 2) Why is it that some of the so-called "accelerated aging" syndromes are thought to be mismatch repair deficiencies, and yet individuals with HNPCC, who also clearly have at least one mismatch repair defect, do not suffer accelerated aging? -- Tim Hughes From owner-ageing@net.bio.net Tue Mar 22 22:00:00 1994 Path: biosci!bcm!cs.utexas.edu!howland.reston.ans.net!torn!nermal.cs.uoguelph.ca!herman.cs.uoguelph.ca!eduda From: eduda@uoguelph.ca (Erika Duda) Newsgroups: bionet.molbio.ageing Subject: Effects of Aging on Bone Date: 23 Mar 1994 00:28:20 GMT Organization: University of Guelph Lines: 16 Message-ID: <2mo2f4$ce4@nermal.cs.uoguelph.ca> NNTP-Posting-Host: herman.cs.uoguelph.ca X-Newsreader: TIN [version 1.2 PL2] Hi there I was wondering if someone could help me out, with a very brief description of how the cortical material in bones changes as a person ages? (the histological changes in rib cortical tissue). I understand it is used with or instead of the morphological changes at the sternal ends of the rib for forensic purposes etc. I've scraped up a couple of papers on it, but it seems pretty cryptic to me (this isn't my area) and not very specific. Perhaps someone could e-mail me a quick explaination (if such a thing exists?) Many thanks Erika eduda@uoguelph.ca From owner-ageing@net.bio.net Tue Mar 22 22:00:00 1994 Path: biosci!bcm!mbcr.bcm.tmc.edu!th035681 From: th035681@mbcr.bcm.tmc.edu (Timothy R. Hughes) Newsgroups: bionet.molbio.ageing Subject: drosophila lifespan Date: 23 Mar 1994 05:01:07 GMT Organization: Baylor College of Medicine, Houston, Tx Lines: 32 Distribution: world Message-ID: <2moiej$em3@gazette.bcm.tmc.edu> NNTP-Posting-Host: mbcr.bcm.tmc.edu I am presenting Sohal's recent paper in Science (sorry I don't have any of these references) reporting extension of drosophila lifespan by addition of SOD and catalase transgenes. I have been looking up his earlier work and I have noticed a discrepancy in fly lifespans and enzyme activities reported. In a previous publication, the average fly lifespan is something like 30 days. But in the publications regarding the transgenics, the control group has a lifespan of about 60 days. The paper says who they got the flies from, but I can't remember the name and nothing came up on medline about long-lived flies when I looked him up. Also, SOD enzyme activities in control groups don't seem to match up well between the papers. I asked around here and was told drosophila usually live about 20-30 days, so I assume the 30 day average is more like a true wild-type lifespan. So where did the control group with a 60 day lifespan come from? Were they already bred for longevity? And what's up with the SOD assay? Help! I know somebody's going to ask me about these things in my presentation. -- Tim Hughes From owner-ageing@net.bio.net Tue Mar 22 22:00:00 1994 Path: biosci!agate!howland.reston.ans.net!pipex!zaphod.crihan.fr!usenet From: PODO@cgmvax.cgm.cnrs-gif.fr (PODO) Newsgroups: bionet.molbio.ageing Subject: Re: DNA damage paradoxes Date: 23 Mar 1994 16:50:11 GMT Organization: CENTRE DE GENETIQUE MOLECULAIRE Lines: 23 Distribution: world Message-ID: <2mps03$1ji@zaphod.crihan.fr> References: <2mngl1$13u@gazette.bcm.tmc.edu> NNTP-Posting-Host: cgmvax.cgm.cnrs-gif.fr X-News-Reader: VMS NEWS 1.24 In-Reply-To: th035681@mbcr.bcm.tmc.edu's message of 22 Mar 1994 19:24:17 GMT In <2mngl1$13u@gazette.bcm.tmc.edu> th035681@mbcr.bcm.tmc.edu writes: > It is most likely that sex has been invented in response to avoid such accumulation of defects in cells. This has been documented in several instances, one of whichn is depicted in a paper by Gilley and Blackburn (P. N.A.S. VOl 91, 1955-1958, 1994).You will also find some information in the book of Bernstein and Berstein: Sex aging and DNA repair. For the moment it is not known whether proteins and other macromolecules can undergo a rejuvenated effect through meiosis but this would be a seducing hypothesis. this could be done in part by increasing translational accuracy in germ cells. second no one knows (or does some one?) the genes that are mutated in the syndrome of premature aging.However, The gene for Werner's has been localised (published last year in nature). So nothing can conclusively be said about the reason of premature aging in these unfortunate persons. The defects seems to be pleitropic as would be mutations in the translational apparatus, transcriptional machinery or DNA maintenance genes. This leaves as you see a lot of room for speculations. Dr; Philippe Silar Centre de genetique moleculaire CNRS/ France From owner-ageing@net.bio.net Wed Mar 23 22:00:00 1994 Path: biosci!barrnet.net!well!mjbrauer From: mjbrauer@well.sf.ca.us (Matthew J. Brauer) Newsgroups: bionet.molbio.ageing Subject: Re: drosophila lifespan Date: 24 Mar 1994 07:38:38 GMT Organization: The Whole Earth 'Lectronic Link, Sausalito, CA Lines: 34 Message-ID: <2mrg1u$120@nkosi.well.com> References: <2moiej$em3@gazette.bcm.tmc.edu> NNTP-Posting-Host: well.sf.ca.us X-Newsreader: NN version 6.5.0 #1 (NOV) th035681@mbcr.bcm.tmc.edu (Timothy R. Hughes) writes: >I am presenting Sohal's recent paper in Science >(sorry I don't have any of these references) reporting >extension of drosophila lifespan by addition of SOD >and catalase transgenes. I have been looking up >his earlier work and I have noticed a discrepancy >in fly lifespans and enzyme activities reported. >In a previous publication, the average fly lifespan >is something like 30 days. But in the publications >regarding the transgenics, the control group has a >lifespan of about 60 days. The paper says who they >got the flies from, but I can't remember the name and >nothing came up on medline about long-lived flies >when I looked him up. >Also, SOD enzyme activities in control groups don't seem >to match up well between the papers. > (...) >-- Tim Hughes > Try searching fro work by Michael Rose, at UC Irvine. He has done some of the most elegant work on aging in Drosophila, and on the evolutionary biology of aging in general. His lines, selected over >10 years had average and maximum lifespans greater than twice those of control lines. Anyone interested in the "reason" for aging should read his work. Matt Brauer From owner-ageing@net.bio.net Wed Mar 23 22:00:00 1994 Path: biosci!agate!howland.reston.ans.net!pipex!sunic!trane.uninett.no!daresbury!not-for-mail From: Newsgroups: bionet.molbio.ageing Subject: Unsubscribe Date: 24 Mar 1994 19:08:43 -0000 Lines: 5 Sender: daemon@mserv1.dl.ac.uk Distribution: bionet Message-ID: <2msofr$46t@mserv1.dl.ac.uk> Original-To: Please take my name off the listserve for aging and bionet. dmcconat@wcu From owner-ageing@net.bio.net Wed Mar 23 22:00:00 1994 Path: biosci!sjubiol.stjohns.edu!rick From: rick@sjubiol.stjohns.edu (Richard Lockshin) Newsgroups: bionet.molbio.ageing Subject: basic aging info for students Date: 23 Mar 1994 23:06:09 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 18 Sender: daemon@net.bio.net Distribution: bionet Message-ID: <9403232056.AA14649@sjubiol.stjohns.edu> NNTP-Posting-Host: net.bio.net [I put this reply in public info because several students and others may be interested. It was in response to a very sweeping question.] One could go on for weeks about these questions. I assume from your .edu address that you are at a US university. You really should go to the library and get some basic books on the subject, for instance, Finch. Otherwise, ask the librarian how to do targeted literature searches. I get the impression that you are using the internet for individual tutorials--not an effective use of academic time. If you have trouble getting started with the literature and you are a student, contact the Gerontological Society of America, 202: 842-1275, 1275 K St NW, Suite 350, Washington DC 20005-4006. They have an effective mentorship program for students who are isolated from gerontological programs. Otherwise, consider going to the GSA meeting in Atlanta the week before Thanksgiving, or the AGE meeting (not yet fixed). --richard lockshin From owner-ageing@net.bio.net Wed Mar 23 22:00:00 1994 Path: biosci!sjubiol.stjohns.edu!rick From: rick@sjubiol.stjohns.edu (Richard Lockshin) Newsgroups: bionet.molbio.ageing Subject: DNA damage paradoxes Date: 23 Mar 1994 23:06:08 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 18 Sender: daemon@net.bio.net Distribution: bionet Message-ID: <9403232054.AA14642@sjubiol.stjohns.edu> NNTP-Posting-Host: net.bio.net [I am putting these replies to Timothy R Hughes on public because I think that others may be interested.] One could go on for weeks about these questions. I assume from your .edu address that you are at a US university. You really should go to the library and get some basic books on the subject, for instance, Finch. Otherwise, ask the librarian how to do targeted literature searches. I get the impression that you are using the internet for individual tutorials--not an effective use of academic time. If you have trouble getting started with the literature and you are a student, contact the Gerontological Society of America, 202: 842-1275, 1275 K St NW, Suite 350, Washington DC 20005-4006. They have an effective mentorship program for students who are isolated from gerontological programs. Otherwise, consider going to the GSA meeting in Atlanta the week before Thanksgiving, or the AGE meeting (not yet fixed). --richard lockshin From owner-ageing@net.bio.net Wed Mar 23 22:00:00 1994 Path: biosci!sjubiol.stjohns.edu!rick From: rick@sjubiol.stjohns.edu (Richard Lockshin) Newsgroups: bionet.molbio.ageing Subject: drosophila lifespan Date: 23 Mar 1994 23:06:03 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 9 Sender: daemon@net.bio.net Distribution: bionet Message-ID: <9403232053.AA14635@sjubiol.stjohns.edu> NNTP-Posting-Host: net.bio.net [I am putting these replies to Timothy R Hughes on public because I think that others may be interested.] Flies under poorly controlled conditions (normal lab conditions) generally live about 30 days, but if kept in low crowding conditions or isolated, and with good food they can do much better. Robert Arking and William Luckenbill at Wayne State, and Michael Rose at Irvine have selected much longer-lived stocks. --richard lockshin From owner-ageing@net.bio.net Wed Mar 23 22:00:00 1994 Path: biosci!sjubiol.stjohns.edu!rick From: rick@sjubiol.stjohns.edu (Richard Lockshin) Newsgroups: bionet.molbio.ageing Subject: apoptosis/cell death Date: 23 Mar 1994 23:06:16 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 12 Sender: daemon@net.bio.net Distribution: bionet Message-ID: <9403232057.AA14656@sjubiol.stjohns.edu> NNTP-Posting-Host: net.bio.net In response to my query, I got lots of comments on defining a happy home for apoptosis, and questions about locating them. In brief: there is currently some apoptosis discussion appearing in aging (ageing@net.bio.net, don't forget the 'e' or British spelling of the word), and its logical home but currently with little discussion is in cell biology (cellbiol@net.bio.net). Either can be subscribed to on email, and various news readers carry whatever is subscribed on the university's service. For the moment I'm following both, and I'll try to keep a crosstalk until it self-selects for a happy home. --richard lockshin From owner-ageing@net.bio.net Thu Mar 24 22:00:00 1994 Path: biosci!KEMI.AAU.DK!RATTAN From: RATTAN@KEMI.AAU.DK Newsgroups: bionet.molbio.ageing Subject: Subscribing to the net Date: 25 Mar 1994 10:23:14 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 10 Sender: daemon@net.bio.net Distribution: bionet Message-ID: <01HADVQGZPBM8WYIOZ@vms2.uni-c.dk> NNTP-Posting-Host: net.bio.net Please include my name in the list of subscribers to this net on ageing. My complete address and e-mail is as follows: Suresh I.S. Rattan Lab. Cellular Ageing Department of Chemsitry Aarhus University DK-8000 Aarhus - >C Denmark e-mail: RATTAN@KEMI.AAU.DK From owner-ageing@net.bio.net Mon Mar 28 23:00:00 1994 Path: biosci!agate!usenet.hana.nm.kr!kuccnx.korea.ac.kr!youngwoo From: youngwoo@kuccnx.korea.ac.kr.korea.ac.kr (±è ¿µ ¿ì) Newsgroups: bionet.molbio.ageing Subject: test Date: 29 Mar 1994 16:54:53 GMT Organization: HANAnet Operating Centre(KTRC) Lines: 5 Message-ID: <2n9mgu$fj7@usenet.hana.nm.kr> NNTP-Posting-Host: kuccnx.korea.ac.kr X-Newsreader: Tin 1.1 PL3 test I'm doing only a test I'll be success. Good Luck to you. From owner-ageing@net.bio.net Wed Mar 30 23:00:00 1994 Path: biosci!ESSEX.HSC.COLORADO.EDU!deutschj From: deutschj@ESSEX.HSC.COLORADO.EDU (John Deutsch) Newsgroups: bionet.molbio.ageing Subject: Subscribing to the net Date: 30 Mar 1994 19:54:19 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 26 Sender: daemon@net.bio.net Distribution: bionet Message-ID: <9403310355.AA03370@essex.hsc.colorado.edu> NNTP-Posting-Host: net.bio.net This section is from the document '/AGEING/current'. From BIOSCI-REQUEST Fri Mar 25 10:23:18 1994 Return-Path: BIOSCI-REQUEST Received: (from daemon@localhost) by net.bio.net (8.6.8.1/8.6.6) id KAA08280 for ageing-list; Fri, 25 Mar 1994 10:23:18 -0800 Received: (from news@localhost) by net.bio.net (8.6.8.1/8.6.6) id KAA08276 for ageing-arpanet; Fri, 25 Mar 1994 10:23:16 -0800 To: ageing@net.bio.net From: RATTAN@KEMI.AAU.DK Subject: Subscribing to the net Date: 25 Mar 1994 10:23:14 -0800 Sender: daemon@net.bio.net Message-ID: <01HADVQGZPBM8WYIOZ@vms2.uni-c.dk> NNTP-Posting-Host: net.bio.net Please include my name in the list of subscribers to this net on ageing. My complete address and e-mail is as follows: Suresh I.S. Rattan Lab. Cellular Ageing Department of Chemsitry Aarhus University DK-8000 Aarhus - >C Denmark e-mail: RATTAN@KEMI.AAU.DK From owner-ageing@net.bio.net Wed Mar 30 23:00:00 1994 Path: biosci!agate!howland.reston.ans.net!pipex!uknet!daresbury!not-for-mail From: weiss@max.muhlberg.edu Newsgroups: bionet.molbio.ageing Subject: subscribe ageing Date: 30 Mar 1994 21:25:11 +0100 Lines: 2 Sender: daemon@mserv1.dl.ac.uk Distribution: bionet Message-ID: <2ncn77$ph3@mserv1.dl.ac.uk> Original-To: ageing I would like to subscribe to ageing. Hayim Seth Weiss From owner-ageing@net.bio.net Thu Mar 31 23:00:00 1994 Path: biosci!bcm!mbcr.bcm.tmc.edu!th035681 From: th035681@mbcr.bcm.tmc.edu (Timothy R. Hughes) Newsgroups: bionet.molbio.ageing Subject: aging FAQ version 1 Date: 1 Apr 1994 22:22:19 GMT Organization: Baylor College of Medicine, Houston, Tx Lines: 540 Distribution: world Message-ID: <2ni6qr$67f@gazette.bcm.tmc.edu> NNTP-Posting-Host: mbcr.bcm.tmc.edu I realize this is painfully incomplete but I promised myself I would post it on April 1 whether I was happy with it or not. I have at least two dozen more articles and several books that have been recommended to me, and I intend to examine all of them in time. The purpose of this FAQ is to address Frequently Asked Questions about the molbio.aging newsgroup. I will post around the first of the month every month. Hopefully this will increase participation, especially by people who read this newsgroup but don't write to it. If you have any thoughts or suggestions, or would like to see any additional topics or specific publications included, please email me at: th035681@mbcr.bcm.tmc.edu Contents include: 1.) brief descriptions of topics generally encompassed, in order to indicate what's going on in general; and 2.) a few references, reviews and/or recent publications regarding topics in aging research. All references should of course be taken to include "and references therein". I am not an expert and this is in part an effort to aid my own understanding of theory and current evidence in aging research. Needless to say this FAQ is biased towards topics I know something about or have been able to locate articles on, and I have omitted descriptions of topics I haven't gotten to yet. It may very well be full of errors and incorrect interpretations, let me know if you think so. I have placed in brackets [] my own thoughts and comments and welcome any response, criticism or help in locating material - if you will, post it on the net and I'll see it there. Thanks, -- Tim Hughes ======================================================================= I. Definition of Aging A. Senescence - Senescence refers to intrinsic adverse changes during aging in an organism. Strictly this is manifest as an increasing likelihood of death as a function of time, measured either from birth or from some developmental stage. [Also, strictly the term "senescence" should be used instead of "aging" in this FAQ but I haven't bothered.] Cell senescence refers to the limited proliferative capacity of cultured somatic cells (see below). 1. Gompertz Curve: A mathematical function called the "Gompertz curve" can be derived to describe expected mortality statistics for a population of organisms whose probability of death increases as a function of time. Many populations (including humans) demonstrate a survival curve which can be fit closely by a Gompertz curve. A critical parameter in the Gompertz expression is the MRDT (mortalitay rate doubling time) which is considered the index of how fast organisms in the population senesce, and it has been suggested that in scientific studies true slowing of the aging process occurs only when the MRDT increases, regardless of other aging parameters (i.e., mean, mode, maximum lifespan). General references on the study of aging: Finch, C. E. 1991. Longevity, Senescence, and the Genome. Univ. Chicago Press. 843 pages including references. Martin, George R. et al. 1993. Aging - Causes and Defenses. Annu. Rev. Med. 44:419-29. A quick overview, not entirely comprehensive but easy reading. Kirkwood, T.B.L. and Cremer, T. Cytogerontology Since 1881: A Reappraisal of August Weismann and a Review of Modern Progress. Human Genetics (1982) 60:101-121. A historical review of aging theories and arguments. II. Theories and evidence regarding the aging of multicellular organisms A. General Arguments. Population genetics [something I know little about] argues that no genetic trait which is detrimental late in life would be selected for, so no genes can survive throughout a population whose sole function is to cause senescence. The remaining possibilites are as follows: 1. Antagonistic Plieotropy: It is possible for genes which are benefical or necessary in youth or in the short term to be detrimental in the long term. An example is the cytochrome oxidase, a metabolic enzyme [detoxifant, I think] which is responsible for the initial step in transforming a number of dietary compounds into mutagenic agents. References: Aeschbacher, H-U. and Turesky, R.J. (1991) Mammalian cell mutagenicity and metabolism of heterocyclic aromatic amines. Mutation Research, 256:235-250. 2. Longevity Assurance Genes: It is also possible that genes which are designed to protect us from detriment be finite in capacity, as no selection may exist for alleles which protect for longer than the lifetime. [Example: genes involved in DNA damage control in somatic tissues.] B. Disposable Soma Theory: It has been suggested that the optimal allocation of energy for an organism which reproduces repeatedly is to invest no more energy in somatic maintenance than is necessary to ensure reproduction. [The original idea, I believe, referred primarily to DNA damage.] [Also, this argument seems unlikely to me to apply to humans. My understanding is that we consume 40% of our resting energy on brain activity, and about 30% of all ATP generated on maintaining transmembrane potentials (from which many cellular processes are driven, I'm not sure how much of that is converted into work and how much is lost by diffusion) and maintain a fairly warm body temperature. This suggests to me that energy conservation is not a significant selective advantage for mammals and humans in particular.] C. Somatic Mutation Hypothesis. DNA is inherently unstable and is susceptible to numerous modification and damaging agents. As genetic material it requires constant maintenance. One of the original ideas about the aging process is that the accumulation of somatic mutations throughout the lifespan is responsible for dysfunction of cells and consequently of organs and individuals. This has fallen out of favor as a mechanism for aging since DNA damage would be expected to be fairly random, and the aging phenomenon is largely consistent between individuals. 2. free radicals: Reactive oxygen species are produced by mitochondria in oxidative phosphorylation, the biochemical pathway that allows us to utilize oxygen in energy production [conversion, rather]. Free radical species can also be produced by ionozing radiation. Free radicals can modify/damage a wide range of cellular molecules including DNA, lipids and proteins. 2. carcinogens and mutagens: 3. cancer: 4. mitochondrial DNA damage: 5. apoptosis: D. Endocrine cascade E. Cell Senescence. In mammalian cells the decision to multiply is made in G1. Cells which pass this "restriction point" will replicate their DNA and then undergo mitosis and divide. A number of types of human cells will undergo less than about 100 divisions when cultured (grown in a dish or flask), at which point the cells adopt a distinctive appearance and will not divide any further. As stimulus to divide in mammalian tissues consists mainly of signaling factors it has been argued that senescence is a tissue culture artifact due to improper or inadequate signaling or an adaptive tolerance to sgnals. In large enough sample sizes, however, an inverse correlation between number of divisions obtained and age of donor is observed. It has been proposed that cell senescence occurs in vivo and could be responsible for loss of homeostasis in tissues of the elderly. Cells which senesce in culture include fibroblasts, lymphocytes, various epithelial cells, and adrenocortical cells. Tumor cells do not senesce in culture and it has also been proposed that senescence acts as a tumor-control mechanism by providing an additional hurdle for growth-errant cells. It is important to note that no direct evidence for cell senescence occuring in vivo has yet been obtained. References: Warner, H.R. et al. (1992) Control of Cell Proliferation in Senescent Cells. Journal of Gerontology 47(6):B185-B189. 1. DNA synthesis inhibition In an expression screen for cDNAs (expressed genes) in senescent cells which could inhibit DNA synthesis in "young" cells, the SDI-1 gene was cloned and found to be significantly up-regulated in senescent cells compered with their young counterparts. The gene was also cloned by two other groups simultaneously using completely different methods, and is thought to be the primary element responsible for p53-dependent cell-cycle arrest. References: Hunter, Tony (1993) Braking the cycle (minireview). Cell 75:839-841 (Dec 3 '93). 2. complementation studies: Cultured cells can be fused to one another and genetic properties analyzed in a manner analagous to yeast mating. Early cell fusion experiments clearly illustrated that senescence was a dominant trait in fused cultured cells (i.e. fusions of young to senescent are senescent; immortal to senescent are senescent.) This suggested that element(s) were missing from immortal cells which could be provided by senescent cells. To determine if immortal cells were all lacking the same thing or had different deletions, various immortal cells were fused, and it was found that some complemented (rescued) each other. In a specific case, a single inserted chromosome was sufficient to restore senescence. These complementation studies have recently been challenged, with apparently different results obtained using somewhat different methods. References: Pereira-Smith, O.M. & Smith, J.R. (1988) Genetic analysis of indefinite division in human cells: Identification of four complementation groups. PNAS 85:6042-6046. Ning, Y. et.al. (1991) Genetic analysis of indefinite division in human cells: Evidence for a cell-senescence-related gene(s) on human chromosome 4. PNAS 88:5635-5639. Ryan, P.A. et al (1994) Failure of Infinite Life span human cells from different immortality complementation groups to yield finite life span hybrids. J. Cell. Phys. (in press) 2. vs. DNA damage: [The fact that senescence is a dominant property suggests that DNA damage is not responsible for the senescence phenomenon. If senescent cells had lost a function that immortal cells retained, then immortality would be dominant. It seems unlikely that senescence would be due to a gain of function mutation in all senescent cells simultaneously. If immortality were due primarily to a gain of function mutation not present in senescent cells, again immortality would be expected to dominate. The remaining possibility then is that immortality is due to a loss of function, and that senescent cells have retained the normal genotype.] 3. telomere shortening: It was originally observed by Crick around 1960 (I think) that the DNA replication machinery, which can only synthesize in one direction, would always leave a little bit of unreplicated DNA on the lagging strand at the telomere (end of the chromosome). Proteins were identified which could extend telomeres, which have a special sequence. It is now well established that human telomeres get shorter on average as a function of age, that they are elongated in sperm cells, that as cells senesce in culture their telomeres shorten with a striking uniformity. It has been proposed that telomere shortening is responsible for cell senescence and hence is involved in the aging process, but no causal role has emerged. Evidence against the telomere hypothesis: Telomere shortening in yeast leads to cell death, not the phenotype seen in mammalian cell senescence; Mouse telomeres are up to ten times as long as human telomeres and do not shorten over the lifetime, and yet mouse cells senesce faster that human cells in culture. References: Kipling, D. & Cooke, H.J. (1990) Hypervariable ultra-long telomeres in mice. Nature 347:400-402. Lundblad, V. & Szostak, J. W. (1989) A Mutant with a Defect in Telomer Elongation Leads to Senescence in Yeast. Cell 57:633-643. Allsopp, R.C. et al. (1992) Telomere Length predicts replicative capacity of human fibroblasts. PNAS 89(21):10114-8. 3. senescence of the immune system: F. Cellular Aging G. Oxidative Stress Hypothesis With the random damage model falling out of favor, the free radical theory has evolved into what is termed the "oxidative stress hypothesis", which asserts that modification and damage to cellular molecules by free radicals is capable of altering "genetic programs" and disrupting cell function, thereby contributing to aging regardless of DNA damage. This model draws support from observations that (1) the free hydroxyl radical can clearly contribute to biochemical pathways producing not only damaged DNA but dysfunctional and/or deleterious proteins and lipids; (2) levels of such "oxidative stress" have been illustrated to increase throughout the lifespans of humans and drosophila [ and c. elegans? ], and is consistent with the results of rodent dietary restriction; (3) there is a clear correlation between lifespan and oxygen consumption/body weight weight in a number of species; (4) recent work in drosophila has extended lifespan by manipulating the biochemical pathway which metabolizes superoxide and hydrogen peroxide. There is extensive literature on oxidative stress. The genes/proteins involved in free radical metabolism are well-known (see SOD, catalase, glutathione peroxidase in any biochemistry textbook) but their regulation is not well understood. [Enzymes are regulated by their substrate and product levels, a "gimme"] Downstream events (i.e., exactly which important proteins and lipids are modified/damaged) is also not clear. References: Sohal, R.S. & Allen, R.G. (1990) Oxidative Stress as a causal factor in differentiation and aging: a unifying hypothesis. Exp. Gerontology 25:499-522. Stadtman, Earl R. (1992) Protein Oxidation and Aging. Science 257:1220-1224. H. DNA methylation Methylation of cytidine residues of DNA has been correlated with gene expression levels in a number of cases. It is unresolved whether methylation is a cause or result of altered chromatin structure. DNA methylation is thought to be responsible for imprinting, and has been implicated as a mechanism in both development and aging. Overall methylation levels in mice apparently decrease as a function of age from six to twenty-four months, and may subsequently increase. There is an extensive literature on DNA methylation and aging studies are only a small part of this active field. References: Singhal, R.P. (1987) DNA methylation in Aging of Mice. Mechanisms of Ageing and Development, 41:199-210. I. Other III. Aging in model organisms Traditional approaches to figuring out how biological systems work include studying mutants, and fractionating extracts and assaying for activity. Generating mutant humans and dissecting them is clearly not as ethical, so traditional laboratory organisms are used in many aging studies. This has an advantage that experiments can be performed ethically and efficiently, but a disadvantage that the results may not apply to humans. Aside from obvious morpohological differences, perhaps the strongest argument is that since humans live so long, our genome must have overcome whatever it is that causes other organisms to have such short lifespans. A. Humans 1. biomarkers of aging in humans: 2. causes of death: I am having a hard time finding a simple summary of U.S. mortality statistics and would appreciate anyone's contribution here. What I have found is that approximately 40% of all persons will have a neoplasm in their lifetime and that for about 20% of the population this is the cause of death. George Will discussed Sherwin B. Nuland's latest book "How We Die: Reflections on Life's Final Chapter" in the March 7 1994 Newsweek, and claimed that 85% of the aging population "succumbs[s] to one of seven ailments - atherosclerosis, hypertension, adult-onset diabetes, obesity, Alzheimer's and other dementias, cancer, and decreased resistance to infections". The book is apparently quite morbid in its attention to detail, and I suppose I will try to find it although I'm frankly not looking forward to reading the thing. 3. progeroid syndromes: a number of hereditary disorders result in short lifespans during which the senescence process is apparently accelerated. None of them exactly matches the wild-type aging phenotype, but the similarities are quite striking, and one would expect genes causing these syndromes to be significant in regulating the aging process. Traditional genetic linkage analyses are difficult because the diseases are very rare autosomal recessive. A linkage for Werner's syndrome was announced two years ago but I haven't heard of a gene yet. A number of progeroid syndromes have been linked to DNA repair deficiencies, and Werner's has a reported mutator phenotype. [The distinction between DNA repair and general transcription and replication is not entirely clear at this point. It is interesting that not all cellular mutator phenotypes result in premature aging syndromes in the organism.] References: Goto, M. et. al. (1992) Genetic Linkage of Werner's syndrome to five markers on chromosome 8. Nature, 355:735-737 (20 Feb '92) 4. linkages to longevity: A recent publication reports the distribution of alleles implicated in cardiovascular risk at two loci (genes) between French centenarians and a control population aged 20-70. The study was quite large and different distributions were found at both loci. The paper refers to an established linkage between longevity and HLA genotype as well. [Also I believe it is common knowledge that women live generally longer than men, making the Y chromosome a significant longevity determinant.] References: Schachter, F. et. al. (1994) Genetic associations with human longevity at the APOE and ACE loci. Nature Genetics 6:29-32 (january 1994). B. Rodents - mice are the most common mammalian experimental model for genetic research. The mouse is considered to to fairly closely model humans. Murine cells are easily transformed in culture. Mice may have fewer defenses against dysplasia because they are smaller and don't live as long. 1. calorie restriction: It was first observed in the 1930's that rats which were fed less but supplied with proper nutrition lived longer. It has since been determined that the caloric intake is the sole determinant, suggesting that metabolic rate metabolic rate serves as a "genetic clock". However, metabolic rate is not necessarily lowered when the reduced mass of the animal is corrected for. The fact that a large number of physiological and pathological symptoms of aging are delayed in CR animals has made the phenomenon difficult to study. As glucose, insulin, and plasma-free glucocorticoid concentrations are affected, modulation of neuroendocrine regulatory systems has been implicated. The onset of tumors, which kill about 50% of all mice, is delayed in CR mice. No direct evidence exists for any hypothesis regarding the effects of CR. References: Masoro, E.J. (1993) Dietary Restriction and Aging. J. of the Am. Ger. Soc. 41:994-999. Weindruch, R. (1989) Dietary Restriction, Tumors, and Aging in Rodents. J. of Geron. 44(6):67-71. 2. SAM (senescence accelerated mouse): 3. SOD transgenics C. Drosophila 1. selected long-lived mutants 2. engineered mutants: An exciting study (which made the New York Times) was published last month in which flies were given extra copies of Superoxide Dismutase, which converts superoxide anion radical to H2O2, and Catalase, which converts H2O2 to water and oxygen. Both mean and maximum lifespan were increased. Transgenics could walk better, and used about 60% as much oxygen towards the end of the lifespan. No effect was seen with either transgene alone. [Why is it that the control flies in this paper lived about 60 days, when wild-type drosophila melanogaster lives about 30 days?] References: Orr, W.C. & Sohal, R.S. (1994) Extension of Life-Span by Overexpression of Superoxide Dismutase and Catalase in Drosophila melanogaster. Science 263:1128-1130 (25 Feb '94) D. C. Elegans - (Nematode worm.) C. elegans is a little worm. It has a good genetic system and lives about a month. It has been a favorite of developmental biologists. The origin and fate of every cell in its body has been mapped. 1. Selected long-lived mutants (age-1, etc.) 2. "Methuselah": A recently reported mutant now holds the record for increase in lifespan. A mutation in daf-2, a developmental gene, more than doubles nematode lifespan (18 to 42 days mean). The mutants are "healthy and fertile". References: Kenyon, C. et al. (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366:461-464. See also News & Views (Pertridge & Harvey) from the same issue. E. Other Species 1. yeast 2. sea urchin 3. calorie restriction in primates F. Relationship of biomarkers of aging in humans to those in model organisms IV. Other interesting phenomena, etc. =================================================================== +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ===================================================================