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Methuselah Prize - You Decide
#61
Posted 01 August 2004 - 01:38 PM
#62
Posted 01 August 2004 - 04:03 PM
But, it's not a bad idea at all. In fact it makes a lot of sense.
1. Design the experiment
2. Source the lab
3. Get a quote for the work
4. Raise the funds
5. Prove the concept
6. Source company to do efficacy studies
7. Do a joint venture
And make money while you find a cure for aging.
The hardest thing would be (4), but for that we have Dave Gobel.
#63
Posted 03 August 2004 - 11:42 PM
Total Votes - 24
Reversal Prize - 13 votes
Postponement & Reversal Prize - 11 votes
Voting and commenting pattern: RP & PP voters seem to be affiliated with the Methuselah Foundation (MF) which of course is not a bad thing but it is predictable seeing as this type of structure captures the most amount of competitors* which is commensurate with the PR objectives of the MF. Naturally, MF supporters will argue that PR is a necessity for building awareness. I am certainly not against building awareness, but surely there are other ways of facilitating this other than compromising research methodology.
It is illuminating that the majority have voted for RP only since their objective seems to be to achieve a solution in the most rapid timeframe possible.
Thus the real issue is this:
How do we maximize promotion without compromising research methodology?/
* when I say "captures" the most amount of competitors, these scientific investigations are occurring irregardless of the existence of the Methuselah Mouse Prize. In practically all cases the researchers primary objective has to do with elucidating specific genetic mechanisms rather than purposefully extending the mouse lifespan.
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#64
Posted 04 August 2004 - 05:37 PM
to do.... so I'm afraid this is also just a quick note.
> Aubrey, what have you heard of Rafal's work over the last year?
He is speaking about it at TV04. I'll let you know.
> The descriptive of "Reversal Prize" is somewhat of a misnomer, having
> come about because the intervention is conducted after the animal is
> born, preferably during adulthood. Once the intervention takes place in
> the mouse, aging processes would be expected to be retarded, stopped or
> reversed - hence Reversal Prize. But reversal is an ideal situation
> which may not be achieved for some time and the fact that it is called
> RP does not preclude interventions designed to retard aging. I invite
> the MethuselahMouse to discuss the choice of names further.
We are in fact doing just this. More anon.
> > As far as I am concerned these changes in cell function can only be
> > effected by manipulating the cell genome.>
>
> How about replacing the cells all together?
Right -- when gene therapy is too hard, use cell therapy instead having
done the genetic modifications in vitro. But I'm not sure prometheus
meant to exclude that from his definition of the reversal prize. Ah yes
-- I now see he goes onto say just that.
> I'm wondering if there are species we can use with shorter lifespans
> than mice, but that still get cancer
This would be nice. There is work now on some fish that appear to age
very quickly and live well under a year despite having a normal gradual
mortality rate increase (unlike salmon):
http://www.ncbi.nlm....t_uids=14667379
In general, the chance of flies telling us any more about mammalian aging
than they already have is rather low, in my view. Just too many things
are built differently, and too many things that go wrong in humans just
have no time to do so in flies (such as clonal expansion of mitochondrial
mutations). In particular:
> What makes you think you can't induce cancer in flies? Simplest way is
> just to knock out a tumor suppressor gene and they develop beautiful
> large tumors in various tissues with all the classic neoplastic
> characteristics. They die from it too.
No, not really. They get something called melanotic tumours, but these
are usually benign (as I understand it) and do not continue growing in
the adult, and moreover (as you say) they only get them when mutated.
> Human dwarves have similarly reduced growth hormone and IGF levels.
> They, however, do not experience any extended lifespan - instead they
> are deformed.
This is a differnt sort of dwarfism. There is an island off Croatia
called Krk where many people have the same genetic defect as in some
of the swarf mice and they do, anecdotally (because recently they all
get growth hormone supplementation) live longer.
> Fly Prize
The biggest problem here, which has not been addressed yet, is diapause.
Flies normally live only a few weeks in the lab, but in the wild they
do perfectly well right through the winter. It's a sort of hibernation,
without any of the morphological oddities seen in the dauer pathway in
worms or sporulation in yeast, but it still multiplies the lifespan by
a large factor (much more than can be explained by the low temperature:
indeed, some species do it when the hours of light per day are reduced
even if there is no change in temperature). It's very hard to see how
to run a prize that disallows diapause.
Aubrey de Grey
#65
Posted 04 August 2004 - 11:11 PM
Also note the number of potential methuselah fly contestants.
Here they are:
1. Exp Gerontol. 2004 Aug;39(8):1137-43.
Metabolic rate is not reduced by dietary-restriction or by lowered insulin/IGF-1 signalling and is not correlated with individual lifespan in Drosophila melanogaster.
Hulbert AJ, Clancy DJ, Mair W, Braeckman BP, Gems D, Partridge L.
Metabolic Research Centre and School of Biological Sciences, University of Wollongong, Wollongong, NSW 2522, Australia.
The link between resting metabolic rate and aging, measured as adult lifespan, was investigated in Drosophila melanogaster by (i) comparing lifespan and metabolic rate of individual flies, (ii) examining the effect of dietary-restriction on the metabolic rate of adult flies, and (iii) comparing the metabolic rate of wild-type and insulin/IGF-1 signalling mutant chico(1) flies. The resting oxygen consumption of 65 individually housed and fully fed Drosophila was measured weekly throughout their lifetime. There was no significant difference in the mass-specific rate of oxygen consumption between cohorts that differed in lifespan. Nor was there any statistical correlation between mass-specific oxygen consumption and lifespan of individual Drosophila. The average mass-specific rate of oxygen consumption at 25 degrees C was 3.52+/-0.07 microl O(2)mg(-1)h(-1). Variation in mass-specific metabolic rate explained only 4% of variation in individual life span in these flies. Contrary to predictions from the 'rate of living' theory of aging lifetime oxygen consumption was not constant and the lifespan of individual flies accounted for 91% of their lifetime oxygen consumption. An average Drosophila consumes about 3 ml O(2) during its adult life. Dietary-restriction had no effect on mass-specific resting metabolic rate both when measured as oxygen consumption by respirometry and when measured as heat production by microcalorimetry. The mass-specific resting heat production of fully fed adult flies at 25 degrees C averaged 17.3+/-0.3 microW mg(-1). Similarly there was no difference in mass-specific metabolic rate of wild-type flies and longliving chico(1) insulin/IGF-1 signalling mutant flies, either when measured as oxygen consumption or heat production. Thus, individual variation in lifespan in wild-type flies, and life extension by dietary-restriction and reduced insulin/IGF-1 signalling is not attributable to differences in metabolic rate.
2: Aging Cell. 2004 Aug;3(4):195-208.
Immunity and aging: the enemy within?
DeVeale B, Brummel T, Seroude L.
Department of Biology, BioSciences Complex, Queen's University, Kingston, Ontario K7L 3 N6, Canada.
Summary Functional analyses of changes in the immune response indicate that aging is associated with a decline of adaptive immunity whereas innate immunity is ramped up. Gene expression studies also support age-dependent changes in immunity. Studies using a large panel of methodologies and multiple species show that some of the most dramatic transcriptional changes that occur during aging are associated with immunity. This observation leads to two fundamental questions: (1) Why is the immune response altered with age? (2) Is this a consequence of aging or does it contribute to it? The origin of these changes and the mechanistic relationship among them as well as with aging must be identified. In mammals, this task is complicated by the interdependence of the innate and adaptive immune systems. The value of invertebrates as model organisms to help answer these questions is presented. This includes a description of the immune response in invertebrate models and how it compares with vertebrates, focusing on conserved pathways. Finally, these questions are explored in light of recent reports and data from our laboratory. Experimental alterations of longevity indicate that the differential expression of immunity-related genes during aging is linked to the rate of aging. Long-lived nematodes are more resistant to pathogens and blocking the expression of immune-related genes can prevent lifespan extension. These observations suggest that the immune response has a positive effect on longevity, possibly by increasing fitness. By contrast, it has been reported that activation of the immune system can reduce longevity upon starvation. We also observed that deregulation of the immune response has drastic effects on viability and longevity in Drosophila. These data suggest that the immune response results in a trade-off between beneficial and detrimental effects that might profoundly affect the aging process. Given this, immunity may be an ally early in life, but turns out to be an enemy as we age.
3: Nature. 2004 Jul 14
Sirtuin activators mimic caloric restriction and delay ageing in metazoans.
Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D.
[1] Department of Pathology, Harvard Medical School, 77 Ave. Louis Pasteur, Boston, Massachusetts 02115, USA [2] These authors contributed equally to this work.
Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD(+)-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.
4: Exp Gerontol. 2004 Jul;39(7):1011-9.
Lifespan extension by dietary restriction in female Drosophila melanogaster is not caused by a reduction in vitellogenesis or ovarian activity.
Mair W, Sgro CM, Johnson AP, Chapman T, Partridge L.
Department of Biology, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
Dietary restriction (DR) extends lifespan in a wide range of organisms. DR also reduces daily and lifetime fecundity. The latter may be an evolutionary adaptation to survive periods of food shortage. Reproductive rate is often negatively correlated with lifespan, and a reduced cost of reproduction could be the mechanism by which DR extends lifespan. We tested this hypothesis in Drosophila melanogaster females, by directly suppressing different aspects of reproduction and measuring the effect on the response of lifespan and age-specific mortality to DR. DR resulted in lifespan extension in females kept with males, in females kept without males, in females with vitellogenesis blocked by the mutant ovo(D1) and in females with no germline as a result of X-irradiation. Moreover, rapid (48 h) changes in age-specific mortality, previously seen in fertile females switched between full feeding and DR, were also seen in ovo(D1) females. Furthermore, these rapid changes in age-specific mortality in cohorts of fertile wild type females were not accompanied by concurrent changes in egg-production. These results indicate either that reduced reproduction is not necessary for lifespan extension by DR in Drosophila females, or that the relevant aspects of reproduction act upstream of our interventions and were therefore not blocked in our experiments.
5: Curr Biol. 2004 May 25;14(10):885-90.
Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.
Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S.
Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125, USA.
In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.
6: Aging Cell. 2003 Apr;2(2):123-30.
Testing an 'aging gene' in long-lived drosophila strains: increased longevity depends on sex and genetic background.
Spencer CC, Howell CE, Wright AR, Promislow DE.
Department of Genetics, The University of Georgia, University of Georgia, Life Sciences Building, Athens, GA 30602, USA. spencer@uga.edu
Molecular advances of the past decade have led to the discovery of a myriad of 'aging genes' (methuselah, Indy, InR, Chico, superoxide dismutase) that extend Drosophila lifespan by up to 85%. Despite this life extension, these mutants are no longer lived than at least some recently wild-caught strains. Typically, long-lived mutants are identified in relatively short-lived genetic backgrounds, and their effects are rarely tested in genetic backgrounds other than the one in which they were isolated or derived. However, the mutant's high-longevity phenotype may be dependent on interactions with alleles that are common in short-lived laboratory strains. Here we set out to determine whether one particular mutant could extend lifespan in long-lived genetic backgrounds in the fruit fly, Drosophila melanogaster. We measured longevity and resistance to thermal stress in flies that were transgenically altered to overexpress human superoxide dismutase (SOD) in the motorneurones in each of 10 genotypes. Each genotype carried the genetic background from a different naturally long-lived wild-caught Drosophila strain. While SOD increased lifespan on average, the effect was genotype- and sex-specific. Our results indicate that naturally segregating genes interact epistatically with the aging gene superoxide dismutase to modify its ability to extend longevity. This study points to the need to identify mutants that increase longevity not only in the lab strain of origin but also in naturally long-lived genetic backgrounds.
7: Biochem J. 2003 Aug 15;374(Pt 1):21-6.
Human sodium-coupled citrate transporter, the orthologue of Drosophila Indy, as a novel target for lithium action.
Inoue K, Zhuang L, Maddox DM, Smith SB, Ganapathy V.
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.
NaCT (sodium-coupled citrate transporter) is an Na(+)-coupled citrate transporter identified recently in mammals that mediates the cellular uptake of citrate. It is expressed predominantly in the liver. NaCT is structurally and functionally related to the product of the Indy (I'm not dead yet) gene in Drosophila, the dysfunction of which leads to lifespan extension. Here, we show that NaCT mediates the utilization of extracellular citrate for fat synthesis in human liver cells, and that the process is stimulated by lithium. The transport function of NaCT is enhanced by lithium at concentrations found in humans treated with lithium for bipolar disorders. Valproate and carbamazepine, two other drugs that are used for the treatment of bipolar disorder, do not affect the function of NaCT. The stimulatory effect of Li+ is specific for human NaCT, since NaCTs from other animal species are either inhibited or unaffected by Li+. The data also suggest that two of the four Na(+)-binding sites in human NaCT may become occupied by Li+ to produce the stimulatory effect. The stimulation of NaCT in humans by lithium at therapeutically relevant concentrations has potential clinical implications. We also show here that a single base mutation in codon-500 (TTT-->CTT) in the human NaCT gene, leading to the replacement of phenylalanine with leucine, stimulates the transport function and abolishes the stimulatory effect of lithium. This raises the possibility that genetic mutations in humans may lead to alterations in the constitutive activity of the transporter, with associated clinical consequences.
8: Biogerontology. 2003;4(3):149-56.
Lifespan extension of Drosophila melanogaster through hormesis by repeated mild heat stress.
Hercus MJ, Loeschcke V, Rattan SI.
Aarhus Centre for Environmental Stress Research, Department of Ecology and Genetics, University of Aarhus, Ny Munkegade, Building 540, DK-8000 Aarhus C, Denmark.
We assessed the impact of repeated episodes of a mild heat stress on lifespan, fecundity, heat stress resistance and Hsp70 expression in Drosophila melanogaster. There was a significant increase in lifespan of females repeatedly exposed to a mild heat stress when measured in both a pair and a group situation. There was no effect on fecundity when the flies were first exposed to the mild heat stress at an age later than 3 days old, but when it did occur on day 3, there was a significant effect on cumulative fecundity levels over 18 days. The negative fitness effect appears to be the result of a direct cessation or reduction of oviposition during the first bout of stress exposure, and is influenced by the age at which this first exposure occurs. The mild heat stress had no impact on egg viability. The mild heat stress exposures increased resistance to potentially lethal heat stress and levels of Hsp70 expression in heat-exposed flies were higher than those in controls.
9: Ageing Res Rev. 2002 Jun;1(3):313-26.
Regulation of lifespan by histone deacetylase.
Chang KT, Min KT.
Neurogenetics Branch (MSC 1250), Building 10, Room 3B12, NINDS, NIH, Bethesda, MD 20892, USA.
Aging is a universal biological phenomenon in eukaryotes, but why and how we age still remain mysterious. It would be of great biological interest and practical importance if we could uncover the molecular mechanism of aging, and find a way to delay the aging process while maintaining physical and mental strengths of youth. Histone deacetylases (HDACs) such as SIR2 and RPD3 are known to be involved in the extension of lifespan in yeast and Caenorhabditis elegans. An inhibitor of HDACs, phenylbutyrate, also can significantly increase the lifespan of Drosophila, without diminution of locomotor vigor, resistance to stress, or reproductive ability. Treatment for a limited period, either early or late in adult life, is also effective. Alteration in the pattern of gene expression, including induction or repression of numerous genes involved in longevity by changing the level and the pattern of histone acetylation may be an important factor in determining the longevity of animals.
10: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2748-53. Epub 2002 Feb 26.
High-quality life extension by the enzyme peptide methionine sulfoxide reductase.
Ruan H, Tang XD, Chen ML, Joiner ML, Sun G, Brot N, Weissbach H, Heinemann SH, Iverson L, Wu CF, Hoshi T, Chen ML, Joiner MA, Heinemann SH.
Department of Biological Sciences, University of Iowa, Iowa City, IA 52242, USA.
Cumulative oxidative damages to cell constituents are considered to contribute to aging and age-related diseases. The enzyme peptide methionine sulfoxide reductase A (MSRA) catalyzes the repair of oxidized methionine in proteins by reducing methionine sulfoxide back to methionine. However, whether MSRA plays a role in the aging process is poorly understood. Here we report that overexpression of the msrA gene predominantly in the nervous system markedly extends the lifespan of the fruit fly Drosophila. The MSRA transgenic animals are more resistant to paraquat-induced oxidative stress, and the onset of senescence-induced decline in the general activity level and reproductive capacity is delayed markedly. The results suggest that oxidative damage is an important determinant of lifespan, and MSRA may be important in increasing the lifespan in other organisms including humans.
11: Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):838-43. Epub 2002 Jan 15.
Life extension in Drosophila by feeding a drug.
Kang HL, Benzer S, Min KT.
Neurogenetics Branch, MSC1250, 10/3B12, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
We report that feeding Drosophila throughout adulthood with 4-phenylbutyrate (PBA) can significantly increase lifespan, without diminution of locomotor vigor, resistance to stress, or reproductive ability. Treatment for a limited period, either early or late in adult life, is also effective. Flies fed PBA show a global increase in histone acetylation as well as a dramatically altered pattern of gene expression, including induction or repression of numerous genes. The delay in aging may result from the altered physiological state.
12: Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14814-8. Epub 2001 Dec 11.
Extension of the Drosophila lifespan by overexpression of a protein repair methyltransferase.
Chavous DA, Jackson FR, O'Connor CM.
Biology Department, Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, USA.
Atypical protein isoaspartyl residues arise spontaneously during the aging process from the deamidation of protein asparaginyl residues and the isomerization of protein aspartyl residues. These abnormal residues are modified in cells by a strongly conserved protein carboxyl methyltransferase (PCMT) as a first step in a repair pathway. Because a decline in cellular repair mechanisms is hypothesized to contribute to senescence, we determined whether increased PCMT activity was correlated with enhanced longevity. Two ubiquitous promoters were used with the binary GAL4-UAS system to drive PCMT overexpression in Drosophila melanogaster. Flies expressing PCMT activity under the regulation of either the hsp70 or actin5C promoter had enzyme activities that were 3- or 7-fold higher, respectively, than control flies at 29 degrees C. Correlated with the observed increases in PCMT activities, such flies lived on average 32-39% longer than control flies. Lifespan extension was not observed at 25 degrees C with either hsp70- or actin5C-driven expression, indicating a temperature-dependent effect on longevity. We conclude that protein repair is an important factor in the determination of lifespan under certain environmental conditions. PCMT activity may become limiting under mild stress conditions that accelerate rates of protein damage.
13: Free Radic Biol Med. 1999 May;26(9-10):1332-8.
Expression of human FALS SOD in motorneurons of Drosophila.
Elia AJ, Parkes TL, Kirby K, St George-Hyslop P, Boulianne GL, Phillips JP, Hilliker AJ.
Program in Developmental Biology, Hospital for Sick Children, Toronto, Canada.
Mutations in human CuZn superoxide dismutase (SOD) have been associated with familial amyotrophic lateral sclerosis (FALS). Although leading to many experimental advances, this finding has not yet led to a clear understanding of the biochemical mechanism by which mutations in SOD promote the degeneration of motorneurons that causes this incurable paralytic disease. To explore the biochemical mechanism of FALS SOD-mediated neuropathogenesis, we used transgenic methodology to target the expression of a human FALS SOD to motorneurons of Drosophila, an organism known for its phenotypic sensitivity to genetic manipulation of SOD. Earlier, we showed that targeted expression of human SOD in motorneurons of Drosophila causes a dramatic extension of adult lifespan (>40%) and rescues most of the phenotypes of SOD-null mutants. Using the same genetic system, we now ask if targeted expression of a mutant allele of human SOD that is associated with FALS causes paralysis and premature death, or is otherwise injurious in Drosophila as it is in humans and transgenic mice. Here we report that high-level expression of a human FALS SOD in motorneurons is not detrimental and does not promote paralysis and premature death when expressed in motorneurons of Drosophila. In sharp contrast, the expression of FALS SOD in Drosophila actually extends lifespan, augments resistance to oxidative stress and partially rescues SOD-null mutants in a manner predicted by our earlier studies on the expression of wildtype human SOD in Drosophila motorneurons.
14: Nat Genet. 1998 Jun;19(2):171-4.
Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons.
Parkes TL, Elia AJ, Dickinson D, Hilliker AJ, Phillips JP, Boulianne GL.
Department of Molecular Biology and Genetics, University of Guelph, Ontario, Canada.
Reactive oxygen (RO) has been identified as an important effector in ageing and lifespan determination. The specific cell types, however, in which oxidative damage acts to limit lifespan of the whole organism have not been explicitly identified. The association between mutations in the gene encoding the oxygen radical metabolizing enzyme CuZn superoxide dismutase (SOD1) and loss of motorneurons in the brain and spinal cord that occurs in the life-shortening paralytic disease, Familial Amyotrophic Lateral Sclerosis (FALS; ref. 4), suggests that chronic and unrepaired oxidative damage occurring specifically in motor neurons could be a critical causative factor in ageing. To test this hypothesis, we generated transgenic Drosophila which express human SOD1 specifically in adult motorneurons. We show that overexpression of a single gene, SOD1, in a single cell type, the motorneuron, extends normal lifespan by up to 40% and rescues the lifespan of a short-lived Sod null mutant. Elevated resistance to oxidative stress suggests that the lifespan extension observed in these flies is due to enhanced RO metabolism. These results show that SOD activity in motorneurons is an important factor in ageing and lifespan determination in Drosophila.
#66
Posted 04 August 2004 - 11:25 PM
1: Ann N Y Acad Sci. 2004 Apr;1014:189-98.
Molecular pathology of the MEN1 gene.
Agarwal SK, Lee Burns A, Sukhodolets KE, Kennedy PA, Obungu VH, Hickman AB, Mullendore ME, Whitten I, Skarulis MC, Simonds WF, Mateo C, Crabtree JS, Scacheri PC, Ji Y, Novotny EA, Garrett-Beal L, Ward JM, Libutti SK, Richard Alexander H, Cerrato A, Parisi MJ, Santa Anna-A S, Oliver B, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ.
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Multiple endocrine neoplasia type 1 (MEN1), among all syndromes, causes tumors in the highest number of tissue types. Most of the tumors are hormone producing (e.g., parathyroid, enteropancreatic endocrine, anterior pituitary) but some are not (e.g., angiofibroma). MEN1 tumors are multiple for organ type, for regions of a discontinuous organ, and for subregions of a continuous organ. Cancer contributes to late mortality; there is no effective prevention or cure for MEN1 cancers. Morbidities are more frequent from benign than malignant tumor, and both are indicators for screening. Onset age is usually earlier in a tumor type of MEN1 than of nonhereditary cases. Broad trends contrast with those in nonneoplastic excess of hormones (e.g., persistent hyperinsulinemic hypoglycemia of infancy). Most germline or somatic mutations in the MEN1 gene predict truncation or absence of encoded menin. Similarly, 11q13 loss of heterozygosity in tumors predicts inactivation of the other MEN1 copy. MEN1 somatic mutation is prevalent in nonhereditary, MEN1-like tumor types. Compiled germline and somatic mutations show almost no genotype/phenotype relation. Normal menin is 67 kDa, widespread, and mainly nuclear. It may partner with junD, NF-kB, PEM, SMAD3, RPA2, FANCD2, NM23beta, nonmuscle myosin heavy chain II-A, GFAP, and/or vimentin. These partners have not clarified menin's pathways in normal or tumor tissues. Animal models have opened approaches to menin pathways. Local overexpression of menin in Drosophila reveals its interaction with the jun-kinase pathway. The Men1+/- mouse has robust MEN1; its most important difference from human MEN1 is marked hyperplasia of pancreatic islets, a tumor precursor stage.
2: Cancer Res. 2004 May 15;64(10):3545-9.
Expression of a novel human gene, human wings apart-like (hWAPL), is associated with cervical carcinogenesis and tumor progression.
Oikawa K, Ohbayashi T, Kiyono T, Nishi H, Isaka K, Umezawa A, Kuroda M, Mukai K.
Department of Pathology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
In Drosophila melanogaster, the wings apart-like (wapl) gene encodes a protein that regulates heterochromatin structure. Here, we characterize a novel human homologue of wapl (termed human WAPL; hWAPL). The hWAPL mRNA was predominantly expressed in uterine cervical cancer, with weak expression in all other normal and tumor tissues examined. hWAPL expression in benign epithelia was confined to the basal cell layers, whereas in dysplasias it increasingly appeared in more superficial cell layers and showed a significant correlation with severity of dysplasia. Diffuse hWAPL expression was found in all invasive squamous cell carcinomas examined. In addition, NIH3T3 cells overexpressing hWAPL developed into tumors on injection into nude mice. Furthermore, repression of hWAPL expression by RNA interference induced cell death in SiHa cells. These results demonstrate that hWAPL is associated with cell growth, and the hWAPL expression may play a significant role in cervical carcinogenesis and tumor progression.
3: Proc Natl Acad Sci U S A. 2004 May 25;101(21):8144-9. Epub 2004 May 14.
Lessons from border cell migration in the Drosophila ovary: A role for myosin VI in dissemination of human ovarian cancer.
Yoshida H, Cheng W, Hung J, Montell D, Geisbrecht E, Rosen D, Liu J, Naora H.
Department of Molecular Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Dissemination of ovarian cancer is a major clinical challenge and is poorly understood at the molecular level due to a lack of suitable experimental models. During normal development of the Drosophila ovary, a dynamic process called border cell migration occurs that resembles the migratory behavior of human ovarian cancer cells. In this study, we found that myosin VI, a motor protein that regulates border cell migration, is abundantly expressed in high-grade ovarian carcinomas but not in normal ovary and ovarian cancers that behave indolently. Inhibiting myosin VI expression in high-grade ovarian carcinoma cells impeded cell spreading and migration in vitro. Optical imaging and histopathologic studies revealed that inhibiting myosin VI expression reduces tumor dissemination in nude mice. Therefore, using genetic analysis of border cell migration in Drosophila is a powerful approach to identify novel molecules that promote ovarian cancer dissemination and represent potential therapeutic targets.
4: Cancer Res. 2004 May 1;64(9):2998-3001.
Three classes of genes mutated in colorectal cancers with chromosomal instability.
Wang Z, Cummins JM, Shen D, Cahill DP, Jallepalli PV, Wang TL, Parsons DW, Traverso G, Awad M, Silliman N, Ptak J, Szabo S, Willson JK, Markowitz SD, Goldberg ML, Karess R, Kinzler KW, Vogelstein B, Velculescu VE, Lengauer C.
Sidney Kimmel Comprehensive Cancer Center and Howard Hughes Medical Institute at Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Although most colorectal cancers are chromosomally unstable, the basis for this instability has not been defined. To determine whether genes shown to cause chromosomal instability in model systems were mutated in colorectal cancers, we identified their human homologues and determined their sequence in a panel of colorectal cancers. We found 19 somatic mutations in five genes representing three distinct instability pathways. Seven mutations were found in MRE11, whose product is involved in double-strand break repair. Four mutations were found among hZw10, hZwilch/FLJ10036, and hRod/KNTC, whose products bind to one another in a complex that localizes to kinetochores and controls chromosome segregation. Eight mutations were found in Ding, a previously uncharacterized gene with sequence similarity to the Saccharomyces cerevisiae Pds1, whose product is essential for proper chromosome disjunction. This analysis buttresses the evidence that chromosomal instability has a genetic basis and provides clues to the mechanistic basis of instability in cancers.
5: Oncogene. 2004 Jul 8;23(31):5263-5.
Make WARTS, not cancer!
Edwards KM, Munger K.
Department of Pathology, Harvard Medical School, Boston, MA 02115-5727, USA.
The WARTS gene encodes a kinase that localizes to the mitotic apparatus of a dividing cell. Named WARTS after the growths that develop in the eyes of Drosophila in which the gene is deleted. WARTS is also implicated as a tumor suppressor in mice and humans. In this issue of Oncogene, Iida et al. describe experiments suggesting that, in addition to a role in regulating mitosis, WARTS functions to prevent further rounds of DNA synthesis and mitosis in tetraploid cells. As well as opening up new possibilities of exploring the as yet ill-defined mechanistic basis of the tetraploidy checkpoint, the involvement of a tumor-suppressor gene in this checkpoint supports its importance as a safeguard against the acquisition of genomic instability, a key event in the progression to cancer.
6: Curr Opin Genet Dev. 2004 Feb;14(1):86-91.
Genes that drive invasion and migration in Drosophila.
Starz-Gaiano M, Montell DJ.
Department of Biological Chemistry, Johns Hopkins Medical Institute, Wood Basic Science Building 413, 725 N Wolfe Street, Baltimore, MD 21205, USA.
Successful cell migration depends on the careful regulation of the timing of movement, the guidance of motile cells, and cytoskeletal and adhesive changes within the cells. This review focuses on genes that act cell-autonomously to promote these aspects of cell migration in Drosophila. We discuss recent advances in understanding the migration of the ovarian border cells, embryonic blood cells, primordial germ cells, somatic gonadal precursors, and tracheal cells. Comparison of genes that regulate these processes to those that promote tumorigenesis and metastasis in mammals demonstrates that studies in fruit flies are uncovering new genes highly relevant to cancer biology.
7: J Cell Physiol. 2004 Jun;199(3):330-58.
Anaplastic lymphoma kinase proteins in growth control and cancer.
Pulford K, Morris SW, Turturro F.
Leukaemia Research Fund Immunodiagnostics Unit, Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. karen.pulford@ndcls.ox.ac.uk
The normal functions of full-length anaplastic lymphoma kinase (ALK) remain to be completely elucidated. Although considered to be important in neural development, recent studies in Drosophila also highlight a role for ALK in gut muscle differentiation. Indeed, the Drosophila model offers a future arena for the study of ALK, its ligands and signalling cascades. The discovery of activated fusion forms of the ALK tyrosine kinase in anaplastic large cell lymphoma (ALCL) has dramatically improved our understanding of the pathogenesis of these lymphomas and enhanced the pathological diagnosis of this subtype of non-Hodgkin's lymphoma (NHL). Likewise, the realisation that a high percentage of inflammatory myofibroblastic tumours express activated-ALK fusion proteins has clarified the causation of these mesenchymal neoplasms and provided for their easier discrimination from other mesenchymal-derived inflammatory myofibroblastic tumour (IMT) mimics. Recent reports of ALK expression in a range of carcinoma-derived cell lines together with its apparent role as a receptor for PTN and MK, both of which have been implicated in tumourigenesis, raise the possibility that ALK-mediated signalling could play a role in the development and/or progression of a number of common solid tumours. The therapeutic targeting of ALK may prove to have efficacy in the treatment of many of these neoplasms. Copyright 2004 Wiley-Liss, Inc.
8: Cell. 2004 Apr 16;117(2):153-6.
Myc: a weapon of mass destruction.
Secombe J, Pierce SB, Eisenman RN.
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Growth and proliferation potentiated by deregulated myc oncogene expression is balanced by myc-induced apoptosis. Abrogation of this apoptotic pathway in Myc overexpressing cells leads to cancer progression. Recent work has shown that cell clones in the Drosophila wing disc with higher dMyc expression levels act as supercompetitors to potentiate the programmed death of surrounding normal cells. Yet another paper identifies dE2F1 as a critical component of pathways that normally restrict the ability of growth perturbing genes like dMyc to cause organ overgrowth.
9: Mol Cell Biol. 2004 May;24(9):3885-93.
p150(Sal2) is a p53-independent regulator of p21(WAF1/CIP).
Li D, Tian Y, Ma Y, Benjamin T.
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
p150(Sal2), a vertebrate homologue of the Drosophila melanogaster homeotic transcription factor Spalt, has previously been shown to be a binding target of the polyomavirus large T antigen. p150(Sal2) acts as an inhibitor of viral DNA synthesis, and the binding of p150(Sal2) by large T overcomes this inhibition. The present study focuses on the effects of p150(Sal2) on the growth and survival of ovarian carcinoma (OVCA) cells that are deficient in expression of p150(Sal2) and of normal established human ovarian surface epithelial (HOSE) cells which abundantly express the protein. Transient expression of exogenous p150(Sal2) in OVCA cells that show little or no endogenous expression resulted in inhibition of DNA synthesis and colony formation and in increased apoptosis. OVCA cells stably transfected and expressing physiological levels of p150(Sal2) showed reduced tumorigenicity accompanied by increased expression of p21(WAF1/CIP1) (p21) and BAX. Conversely, reduction of endogenous levels of p150(Sal2) in HOSE resulted in reduced p21 expression and increased DNA synthesis. p150(Sal2) bound to the p21 promoter adjacent to the known p53 binding sites and stimulated transcription in the absence of p53. We propose that p150(Sal2), acting in part as a p53-independent regulator of p21 and BAX, can function in some cell types as a regulator of cell growth and survival.
10: Oncogene. 2004 Apr 12;23(16):2809-18.
To die or not to die: how does p53 decide?
Slee EA, O'Connor DJ, Lu X.
Imperial College School of Medicine at St Mary's, Ludwig Institute for Cancer Research, Norfolk Place, London W2 1PG, UK.
p53 is frequently mutated in cancer and as a result is one of the most intensely studied tumour suppressors. Analysis of the primitive forms of p53 found in Caenorhabditis elegans and Drosophila, alongside studies using transgenic mouse models, indicate that the induction of apoptosis is both the most conserved function of p53 and vital for tumour suppression. p53-mediated apoptosis occurs through a combination of mechanisms which include pathways that are both dependent and independent of alterations in gene expression. In response to genotoxic insult, these pathways probably act together, thereby amplifying the apoptotic signal. However, the picture is complicated because the p53 activity is determined by stress type and individual cellular characteristics. The numerous p53 responsive genes that have been identified also provide further means of controlling the actions of p53. The recent discoveries of proteins that interact with p53 and specifically regulate the ability of p53 to trigger apoptosis have provided further mechanistic insights into the role of p53 in inducing cell death. Understanding the molecular basis of the proapoptotic action of p53 can assist in our quest to reintroduce or reactivate p53 in human tumours.
#67
Posted 05 August 2004 - 12:07 AM
Furthermore I have yet to fathom why it is that technically sound strategies suggested to accelerate discovery and human intervention development such as:
1. Focusing on the RP
2. Launching a Methuselah Fly Prize
Are being ignored in the name of "PR".
So we must ask how it is that a superior strategy impacts on PR, and if indeed it does (I remain unconvinced that it does) how a solution can be found that does not have to sacrifice technique for PR.
And for those who have been following these debates, you will find we have come full circle since we are compelled to question what is the primary objective of the MF - accelerate progress towards real longevity-enhancing medicine or PR?
Can these objectives become aligned in the context of the optimal technical solution or do they then become diametrically opposed?
#68
Posted 05 August 2004 - 11:44 AM
Many thanks again. You are of course quite right that the gerontological community has
no difficulty with diapause, any more than dauer. You must bear in mind, however -- and
I speak as one of that community, so I'm not being catty here -- that the whole process
of peer-reviewed scientific publication inherently entrenches conventional wisdom. I have
a paper in press which starts from pointing out that we have no logical reason to regard
diapause and dauer as irrelevant to starvation-induced life extension in mammals, and
concludes that CR and its emulation in humans will probably extend our lifespan by only
a couple of years at best. This conclusion may be wrong, but it's carefully argued (as it
had to be, to withstand unsurprisingly quite hostile reviewers) and if it's right then those
who are ploughing millions into Elixiir and so on are going to be rather disappointed. I
anticipate a big fight about this in the coming year.
Coming back to the Methuselah Fly Prize idea: if we were awarding a prize for a published
study, rather than for a single fly, there might not be much problem (precisely because of
the conventional wisdom just mentioned). But if a single fly lives verifiably six months,
how are you going to show that it didn't spend a lot of that time in a diapause-like state?
You can't run tests every week to check its juvenile hormone levels... There seems indeed
to be a lot more heterogeneity of lifespan in published studies of flies than mice (see Carey
and Curtsinger's famous studies from 1992 for example) and this may very well be because
the diapause pathway gets constitutively activated to a partial degree by purely adventitious
epigenetic factors.
Let me not give the impression that I dispute your goals here, prometheus -- anything we
can do that benefits the overall goal of expediting human life extension, whether by PR or
any other means, is welcome, period. All we need to avoid is diluting the currently very
limited resources at our disposal (I mean those of whole pro-life extension community, not
just the MF) with initiatives that sound good at first but fail in the detail. If I thought we had
any chance of expediting human life extension with a Methuselah Fly Prize, I'd be all for it,
and I remain open to persuasion, no question -- but the problems I've set out are severe,
in my current view.
#69
Posted 05 August 2004 - 05:37 PM
The age related alterations in gene expression are largely triggered by DNA damage and the pathways activated by CR ultimately lead to an increase in DNA repair and production of anti-oxidants providing support for the basis by which CR induces its life extending effects.
How are you able to reconcile the observations of substantial lifespan extension in model organisms ranging from yeast to primates with your assertion of only minimal lifespan increased due to CR? Studies in mammals have demonstrated substantial mitigation in age related disease processes due to the effects of CR. I must say that on this point it is not difficult to side with the reviewers. I am looking forward to reading your reasoning in your upcoming article.
You say that the problems you have set out in respect to a Methuselah Fly Prize are severe. Yet I gather that your main point of contention is with estimating the efficacy of a life extension intervention in flies due to the potential ambiguity in differentiating diapause from intervention in the total lifespan. I am sure that any investigator would be looking to also publish or patent results and would consequently still need to be subjected to the scrutiny of the peer review process. Furthermore, engaging the competitors to participate in a daily reporting mechanism would provide content for the website as well as a means of monitoring the progress of the animals. Incidentally, due to the quantity of flies that can be screened in parallel there is no reason why a number of animals could not be analyzed on a weekly or other frequency basis for determining duration of any diapause events.
I hope that I am not coming across as being argumentative - I am simpy keen to seek a solution. Aside from this concern of measuring efficacy of intervention in the context of a diapause state, is there any other issue that you have with using drosophila?
How is it that you believe that this research cannot be expedited by using drosophila?
#70
Posted 05 August 2004 - 06:48 PM
I'll defer to Prometheus's response, then add my two cents:...if we were awarding a prize for a published study, rather than for a single fly, there might not be much problem (precisely because of the conventional wisdom just mentioned). But if a single fly lives verifiably six months, how are you going to show that it didn't spend a lot of that time in a diapause-like state?
Another thing to consider is that we don't have to lock ourselves into the single subject paradigm when awarding the prize. With mice, this paradigm is valid for a couple reasons obvious to me as an outsider (non-gerontologist):Yet I gather that your main point of contention is with estimating the efficacy of a life extension intervention in flies due to the potential ambiguity in differentiating diapause from intervention in the total lifespan. I am sure that any investigator would be looking to also publish or patent results and would consequently still need to be subjected to the scrutiny of the peer review process. Furthermore, engaging the competitors to participate in a daily reporting mechanism would provide content for the website as well as a means of monitoring the progress of the animals. Incidentally, due to the quantity of flies that can be screened in parallel there is no reason why a number of animals could not be analyzed on a weekly or other frequency basis for determining duration of any diapause events.
1) Mice lifespans are considerably more well-behaved. They have well-defined increasing age-dependent mortality rates. Being warm-blooded, they are not as affected by temperature as insects are. And of course, no diapause.
2) It's expensive to run an experiment with 100 mice, let alone 500 or a thousand. With fewer mice, the chance of a dramatic statistical outlier is reduced; on the other side, picking a target such as the top decile or the top 5% of lifespans will inherently be inaccurate given the small sampling size.
With flies, on the other hand, we can use a different paradigm. Rather than awarding individual "flies", we could award experimental groups: peer-reviewable studies. I say reviewable, as opposed to reviewed, because it may indeed be the committee awarding the fly prize that is doing the review; it need not be an outside peer-reviewed journal sub-committee.
Of course, as Prometheus pointed out, those competing will have every incentive to go for double credit--to run an experiment that will make it into a peer-reviewed journal, and to try to win the fly prize.
We can set the criteria however we want, to strike a balance between scientific credibility, ease for the competitors, and public appeal.
After all, creating one fly that lives 150 days in an experimental group where the other 850 flies died in less than 120 days, is not lending anyone the impression of credibility: not the fly prize, and certainly not the researcher involved.
However, if we based the results on top 5%, top decile, or mean adult lifespan, and if we required frequent (daily, weekly, etc.) reporting by registered competitors, then credibility can be maintained.
For those who do not report frequently (or do not even register to compete until after they've completed their experiment), we can always run the experiment again! As Prometheus has pointed out in the past, the lifespans involved are short enough for second-party validation. Supply us with the eggs or larvae, and we'll do the rest. If we are in the unfortunate position of having to wait 8 months to verify what appears to be an outrageous claim of that length, I'm not going to complain...
Jay Fox
#71
Posted 05 August 2004 - 06:53 PM
I will post some links to these posts in that topic. We should move any remaining replies (with appropriate quotes to maintain context) there.
Thanks much!
Jay Fox
#72
Posted 12 August 2004 - 05:13 PM
very rushed right now, but just to point out that Jay seems to be overlooking the fact that
someone can start today an experiment with mice that are already (say) 3.5 years old and
thereby win the RP 18 months from now if any mouse reaches 5 years old. This is one of
the main selling-points of using aspartate racemisation to validate age: we don't need to
have seen the mouse when it was young.
#73
Posted 12 August 2004 - 10:06 PM
The other issue is finding a supplier of late life mice whose history of diet, activity, etc. can be verified. It's not like you can call Biolabs and order 30 white lab mice that are 24 months old and have been fed on a particular diet. Unless you have a reliable source, you have to raise to them to that age in your own lab which unfortunately constrains us to the experimental timespans estimated by Jay.
#74
Posted 14 August 2004 - 02:26 AM
*RP candidate:*
Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5524-9. Epub 2004 Mar 25.
Temporal linkage between the phenotypic and genomic responses to caloric restriction.
Dhahbi JM, Kim HJ, Mote PL, Beaver RJ, Spindler SR.
BioMarker Pharmaceuticals, Incorporated, 900 East Hamilton Avenue, Campbell, CA 95008, USA.
Caloric restriction (CR), the consumption of fewer calories while avoiding malnutrition, decelerates the rate of aging and the development of age-related diseases. CR has been viewed as less effective in older animals and as acting incrementally to slow or prevent age-related changes in gene expression. Here we demonstrate that CR initiated in 19-month-old mice begins within 2 months to increase the mean time to death by 42% and increase mean and maximum lifespans by 4.7 (P = 0.000017) and 6.0 months (P = 0.000056), respectively. The rate of age-associated mortality was decreased 3.1-fold. Between the first and second breakpoints in the CR survival curve (between 21 and 31 months of age), tumors as a cause of death decreased from 80% to 67% (P = 0.012). Genome-wide microarray analysis of hepatic RNA from old control mice switched to CR for 2, 4, and 8 weeks showed a rapid and progressive shift toward the gene expression profile produced by long-term CR. This shift took place in the time frame required to induce the health and longevity effects of CR. Shifting from long-term CR to a control diet, which returns animals to the control rate of aging, reversed 90% of the gene expression effects of long-term CR within 8 weeks. These results suggest a cause-and-effect relationship between the rate of aging and the CR-associated gene expression biomarkers. Therefore, therapeutics mimicking the gene-expression biomarkers of CR may reproduce its physiological effects.
#75
Posted 14 August 2004 - 04:52 AM
Neat!...tumors as a cause of death decreased from 80% to 67% (P = 0.012).
This is probably old news, but it's a detail I've wondered about and never seen the evidence for. I knew that, in CR'd mice, all the leading causes of death were reduced when compared to non-CR'd mice of the same age. However, I couldn't remember any statistics on whether certain causes of death were better modulated than others.
I've always assumed that, if the leading age-related causes of death were to some extent caused by ROS-induced damage, then cancer in the overall scheme of things would be reduced relatively more than the other leading causes in CR'd mice. But until now, I'd never seen the numbers proving it.
That's really neat! I'd be interested to know the disease-specific mortality rates for the top three or four causes of death--not just in percentages, but as their actual rates. But they always seem to give the highlights in these abstracts, and the best details, if present at all, are in the studies.
By chance, Prometheus, are there such details in the full text?
Jay Fox
#76
Posted 14 August 2004 - 05:13 AM
(Never too late to start modulating the CR axis)
*RP candidate:*
...
Here we demonstrate that CR initiated in 19-month-old mice begins within 2 months to increase the mean time to death by 42% and increase mean and maximum lifespans by 4.7 (P = 0.000017) and 6.0 months (P = 0.000056), respectively.
Definitely close to being able to compete in the RP category, but as I've pointed out, the increase in maximal time to death should be close to, if not more than, 100%. How the increase in maximal time to death correlates with the increase in mean time to death, I cannot say. But I assume some of the biologists here can confirm that if the latter is 42%, the former will most likely not be anywhere near 100%?
I can only see one possible way that a 42% mean increase would correlate with a much larger maximal increase. I'm assuming the mean time to death is in the neighborhood of 11 months, given that 4.6 months is about 42% more than the mean time to death. If considering only the mice that died at or before the mean time to death, the mice were started on CR having lived 19 of their 30 or fewer months. CR at this point might not benefit them, because given that they died before those mice that reached maximum age, we can in hindsight speculate that they had already accumulated a larger amount of age-related damage by 19 months. That damage may not be benefitted by CR, and the continuing damage caused by this advanced state of cellular damage may be beyond the ability of CR to fix, even with up-regulated DNA-repair factors and antioxidants.
On the other hand, with the mice that lived to maximum age, we can assume in hindsight that their bodies had accumulated less age-related damage by 19 months, and that CR had a larger ability to both prevent further new damage, as well as further damage due to existing damage (e.g. damaged mitochondria with ROS production rates many times higher than normal, leading to higher damage rates).
In this scenario, I would certainly expect the CR'd mice that reached maximum age to have gained a larger absolute lifespan extension. However, I'm still not convinced that there will be a much larger relative extension, for the following reason. If the longer-lived mice benefitted more from CR because they had less damage to begin with, then we should expect to see larger relative gains in mice that are started on CR diets earlier. But we don't. Larger absolute gains, to be sure, but I seem to recall relative gains on extreme CR diets not being much better than 42% when started from weaning. In fact, even reaching 42% often involved levels of CR so high as to lead to premature deaths along the way, so that while maximum lifespan was greatly increased, mean lifespan was only moderately increased.
Anyway, I've belabored this point. Bottom line, these mice would make a welcome addition to the RP prize, if for no other reason than to show that real research projects in this area are under way. However, I'm not holding my breath on the results.
Jay Fox
#77
Posted 14 August 2004 - 02:25 PM
and
concludes that CR and its emulation in humans will probably extend our lifespan by only
a couple of years at best.
Following the ideas in previous post, I'll show a few studies that suggest CR should extend human lifespan significantly:
Let's start by viewing long lived human relatives:
A study of children whose parents lived 100 years or more is helping researchers understand contributors to longevity as well as separate environmental from genetic factors. And it has already produced an important finding: The kids have a strikingly lower incidence of heart disease, but not of many others.
Reported at the American Heart Association's Scientific Sessions 2002, the study compared 176 children of centenarians with 166 controls whose parents were born in the same year but died at 73, the average life expectancy for that group.
The average age of the centenarians' children was 71.1 years, while the average for the control group was 69.7 years.
On many measures, the children of centenarians demonstrated health advantages. These included:
* Blood pressure: Children of centenarians had a lower incidence of high blood pressure (26% compared to 52%)
* Heart disease: Their incidence of heart disease was far lower (13% compared to 27%)
* Diabetes: Their incidence of diabetes was less than half (5% compared to 11%)
* Weight: They had a lower average weight and a lower body mass index (weight was 146 lbs. compared to 158 lbs. for females, 184 lbs. compared to 202 lbs. for males)
Controlling for differences in education, however, the study did still find major differences in cardiovascular disease. But for many other diseases -- including cancer, stroke, dementia, osteoporosis, cataracts, glaucoma, macular degeneration, depression, Parkinson's disease and thyroid disease -- there was little difference
Now let's see some more:
Lower serum glucose and low insulin levels are among the dramatic biomarkers of slower aging in calorie-restricted animals. This effect very likely applies to humans. A massive National Institute of Health study has already established that older men with the lowest insulin are the healthiest. Low-normal blood sugar generally goes hand-in-hand with healthy-range blood lipids.
Other relevant data:
PHILADELPHIA (Reuters) - Overweight people can reduce their risk of death by trying to lose weight, regardless of whether they actually succeed in shedding pounds, a U.S. government health study suggested on Monday.
Researchers at the U.S. Centers for Disease Control and Prevention (news - web sites) tracked the cases of 6,391 overweight and obese people who joined the National Health Interview Survey over a nine-year period from 1989 to 1997.
What they found was a 24 percent drop in mortality among people who lost weight intentionally, compared with others who maintained a stable body mass without seeking weight loss. Mortality rates shrank by a steeper 30 percent among those who managed to lose between 2.2 pounds and 19.8 pounds.
Even those who tried to become thinner and failed saw their mortality rates fall 19 percent, leading researchers to wonder whether the attempt to lose weight can be seen as a marker for other healthy behaviors that can lower mortality.
The study, published in the American College of Physicians' Annals of Internal Medicine, provided the clearest evidence yet that intentional weight loss can reduce the risk of death.
While links between obesity and life-threatening diseases such as diabetes, heart disease and cancer are well established, CDC researchers said some studies up to now have suggested that losing weight can lead to higher mortality.
Earlier findings may have been skewed by unintentional weight loss linked to health problems including cancer, heart disease and depression, CDC researchers said.
People in the study who lost weight without trying saw mortality rates shoot up by as much as 77 percent.
Now for another study, recall the centenarian children study, which correlates with what's seen on actual centenarians, and the other one showing low glucose indicates good health in old humans:
The study included 18 people who belong to an organization called the Calorie Restriction Optimal Nutrition Society. The group advocates consuming between 10% and 25% fewer calories than is considered normal while being careful to maintain proper nutrition. Men in the group typically eat fewer than 2,000 calories a day and women eat fewer than 1,500.
The findings are published in the April 27 issue of the Proceedings of the National Academy of Sciences.
The calorie-restricted group had blood levels of "bad" LDL cholesterol in the lowest 10 percent of people in their age group. The readings for "good" HDL cholesterol, which carries fats out of the arteries, were in the highest 15 percent of their age group. And their levels of triglycerides, fats that contribute to atherosclerosis, were LOWER than in 95 percent of Americans HALF THEIR AGE.
Holloszy’s team found the two groups not only differed in the number of calories consumed, but also in the composition of their diets. Individuals in the calorie restriction group ate between about 1,100 and 1,950 calories per day depending on height, weight and gender, and these calories consisted of about 26 percent protein, 28 percent fat and 46 percent complex carbohydrates. In contrast, the comparison group consumed between about 1,975 and 3,550 calories per day, with only 18 percent of their calories from protein, 32 percent from fat and 50 percent from carbohydrates, including refined, processed starches.
Atherosclerosis — clogged arteries that can lead to a heart attack or stroke — already is the leading cause of death in the Western world, and the problem is continuing to grow. So Holloszy’s team specifically focused on the risk factors for this condition. They measured multiple indications of early or impending atherosclerosis, including blood pressure and levels of several biological markers in the blood, including cholesterol and triglycerides. They also measured the levels of glucose and insulin in the blood to gauge diabetes risk, another major health concern in the American population.
People in the calorie restriction group had total and low-density lipoprotein — known as LDL or “bad” cholesterol — levels comparable to the lowest 10 percent of the population in their respective age groups. Their high-density lipoprotein — known as HDL or “good” cholesterol — levels were in the 85 to 90 percentile for middle-aged men. That finding was a surprise because HDL levels typically decrease when individuals follow low-fat diets to lose weight.
Triglyceride levels — which, when elevated, can lead to atherosclerosis — were even more impressive in the calorie restriction group: They were lower than more than 95 percent of Americans in their twenties, despite the fact that the study participants’ ages ranged from 35 to 82.
In contrast, cholesterol and triglyceride levels in the comparison group were in the 50th percentile for average middle-aged Americans. Moreover, 12 of the individuals in the calorie restriction group provided medical records from before and during the diet. Their cholesterol and triglyceride scores also were close to the 50th percentile for middle-aged Americans before the diet, and levels fell the most dramatically during their first year of calorie restriction.
Blood pressure scores in the restricted group also were equivalent to those of much younger individuals. The average blood pressure in the normal diet group was about 130/80, which is standard for the typical American. In comparison, the calorie restriction group’s average was about 100/60, akin to the blood pressure of an AVERAGE 10-YEAR-OLD.
Fasting glucose and insulin — both markers of the risk of developing diabetes — also were SIGNIFICANTLY LOWER in the calorie restriction group, with insulin concentrations as much as 65 percent lower.
All other risk factors measured also were SIGNIFICANTLY BETTER in the calorie restriction group. They included body mass index, body fat mass, C-reactive protein and the thickness of the carotid artery, the main blood vessel that runs from the heart to the brain.
“These effects are all pretty dramatic,” Fontana says. “For the first time, we’ve shown that calorie restriction is feasible and has a tremendous affect on the risk for atherosclerosis and diabetes.”
A quote from John O. Holloszy, the lead research for this study: "These people are definitely protected against the major killers. It should definitely increase longevity."
Another quote from the same study
(Reported by The Herald). The Proceedings of the National Academy of Sciences has published an impressive set of statistics on the effects of calorie restriction (CR) in humans, based on ongoing US research. It makes for compelling reading: "It's very clear from these findings that calorie restriction has a powerful protective effect against diseases associated with ageing. [Practitioners will] certainly have a much longer life expectancy than average because they're most likely not going to die from a heart attack, stroke or diabetes." The study subjects, with an average age of 50, had blood pressure readings akin to those of a 10 year old! If you can't sell calorie restriction with a statistic like that, then you can't sell calorie restriction.
Now as we see, the genetic benefits received by centenarian kin, are akin to those received by CR, but CR seems to actually exceed them in degree. This data suggests that CR should increase lifespan in average humans to at least centenarian scales, maybe slightly moreso.
Edited by apocalypse, 14 August 2004 - 02:49 PM.
#78
Posted 15 August 2004 - 12:55 AM
If possible, when quoting comments made here at ImmInst, could you include the name/handle of the person(s) making the statements? I.e., use something like "[quote]" as opposed to just using "[quote]".
I figured that first quote (about CR giving a couple years at best) was made by Dr. de Grey (ag24), but I had to search for it to be sure. After all, perhaps someone else was quoting Dr. de Grey, and you were quoting, and therefore trying to correct/educate, that person, not Dr. de Grey.
I'm not trying to be crabby, just thought it might help prevent confusion...
Jay Fox
#79
Posted 16 August 2004 - 10:05 AM
average lifespan = human(85 yrs) = mouse(2.5 yrs) = fly(0.2)
If we look at the best that has been achieved to date in mice which the 4 years by Yoda, then the equivalent age in humans is 136 years.
I am very annoyed for allowing myself to get so involved in some debates of no consequence that I neglected to report on what is an additional issue in the MMP and further supports the futility of a PP in mice (but not in flies):
It relates to what has already been achieved in mice in terms of lifespan, namely 4 years in mice or the equivalent of 136 years in humans.
We already have already demonstrated fundamental progress in a stage 1 lifespan extension in mammalian systems (Yoda).
The emphasis must be on transforming this existing scientific discovery into human interventions.
Rather than wasting time with PP-type research in mice we must focus our attention to RP-type research in mice, particularly converting existing discoveries into adult mammalian interventions.
#80
Posted 16 August 2004 - 03:43 PM
Both Yoda and Bartke's mouse generated very significant and positive publicity...leading to increased funding for the prize and millions of media impressions to help prepare and sway public opinion (we need many billions of impressions, but it's a good start).
My current belief is that PP has given us an incredibly useful start ridiculously out of proportion to its "cost" and will continue to do so for a while.
#81
Posted 17 August 2004 - 02:19 AM
A week short, in fact. Pity, really: the publicity probably would have been half again as big had the mouse made it to the 5-year-mark....which lived to 1819 days. Nearly 5 years I believe.
Jay Fox
#82
Posted 17 August 2004 - 02:43 AM
#83
Posted 05 September 2008 - 08:43 PM
#84
Posted 10 September 2008 - 03:42 PM
You must remember when asking this question, even if you do put research into PP, it will take years until it is feasible, doing so and dismissing RP will claim the lives those who are already alive.
But is that all?
The answer is, no. not only the living will be claimed but also those who are born before the therapies arrive and even then, not all will know and not all can afford.
Some newborn will be chosen to die by their parents having no choice on being altered for life before birth.
Is this the way we really want it?
Who is this we want to save, the living or the not yet alive? which actually means only those lucky enough to have their parents informed and with a brain instead of faith or any other reason preventing most humans to choose life.
While saving the living, will later save those who are not yet here, with no hesitation, I vote for RP only.
Edited by Winterbreeze, 10 September 2008 - 03:46 PM.
#85
Posted 02 December 2008 - 12:20 PM
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