ISSN 0964-5659

Longevity Report 60

Volume 11 no 60. First published July 1997. ISSN 0964-5659.

e-mail: Internet longevityrpt@yahoo.com



Parental Predictors of Human Longevity. Leonid A.Gavrilov and others

Comparison of Maternal and Paternal Effects on Human Longevity Leonid A.Gavrilov and others

Letter

Fruit Fly Experiments Douglas Skrecky

As others see us New Hope International

Microtech Or Nanotech ? Yvan Bozzonetti

Is Ignorant Freedom A Good Or Bad Thing? Brent Allsop

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Parental Predictors of Human Longevity.



by Leonid A.Gavrilov, Natalia S.Gavrilova, Galina N.Evdokushkina, Victoria G.Semyonova, Anna L.Gavrilova, Natalia N.Evdokushkina, Yulia E.Kushnareva, Alexander Yu.Andreyev, Vyacheslav N.Kroutko A.N.Belozersky Institute, (email: leonid@gavrilov.genebee.msu.su) Moscow State University, Moscow, Russia and Institute for Systems Analysis, Russian Academy of Sciences, Moscow (email: gavrilov@glas.apc.org)



One of important approaches to understand the mechanisms of human longevity is to study an association between parental characteristics (paternal and maternal ages at reproduction and at death) and longevity of their children. In our previous studies we have found a strong inverse relationship between father's age at reproduction and daughter's (not son's) longevity1,2. This finding is in accord with the mutation theory of aging3 since paternal age at reproduction is considered to be the main factor determining human spontaneous mutation rate4,5. Also, since only daughters inherit the paternal X chromosome, this sex-specific decrease in longevity of daughters born to old fathers might indicate that human longevity genes (crucial, house-keeping genes) sensitive to mutational load might be located in this chromosome1,2.



It should be noted however that in the previous preliminary studies1,2 the effects of paternal age at reproduction were not controlled for the effects of other important covariates and confounding factors: maternal age at reproduction (which is closely related to paternal age), historical trends and fluctuations in life expectancy of birth cohorts as well as parental longevity (age at death). The purpose of this particular study is to fill this gap and to check the previous preliminary observation on the life-shortening effects of late paternal reproduction taking into account other important covariates mentioned above.



In this study we have collected, computerized and analyzed the genealogical data on human longevity in more than 700 different European royal and noble families published in the famous edition Genealogisches Handbuch des Adels6 and in other 120 professional genealogical sources, listed elsewhere7. Offspring life span was analyzed for adults (those who survived by age 30) in order to study the long-term, postponed effects of late reproduction of the parents. The data for offspring born in 20th century was excluded from the analysis in order to have unbiased estimates of longevity for extinct birth cohorts. The data for offspring born before 19th century was also excluded in order to minimize the heterogeneity of the sample. For each birth cohort the mean sex-specific expectation of life at age 30 was calculated and used as an independent variable in multiple linear regression to control for cohort and secular trends and fluctuations in human longevity. Offspring longevity for each particular sex (4566 records for males and 2068 records for females) was considered as a dependent variable in multiple regression model (program 1R in BMDP statistical package) and a function of 5 independent predictors: paternal age at reproduction in the range of 35-55 years (where the life-shortening effect was previously detected1,2, maternal age at reproduction (control for maternal age is important since it is correlated with paternal age), paternal age at death, maternal age at death (to control for heritability of human longevity) and sex-specific cohort life expectancy (control for cohort and secular trends and fluctuations). The detailed description of the sample under study is given in the Table 1.
Table 1.

Characteristics of the sample under study.

Variable Sons Daughters
Sample size 4566 2068
Offspring birth dates
range: 1800-1899 1800-1899
mean: 1860.6 1864.7
standard deviation: 25.2 27.9
Offspring age at death
- range: 30-100 30-105
- mean: 64.6 73.5
- standard deviation: 14.9 15.6
Paternal age at reproduction
- range: 35-55 35-55
- mean: 41.4 41.6
- standard deviation: 5.1 5.2
Maternal age at reproduction
- range: 16-56 15-51
- mean: 30.7 31.0
- standard deviation: 5.7 5.8
Paternal age at death
- range: 35-99 35-96
- mean: 68.2 68.4
- standard deviation: 12.0 12.0
Maternal age at death
- range: 21-102 19-102
- mean: 68.8 69.2
- standard deviation: 15.6 15.8
Cohort life expectancy
- range: 58.0-72.5 56.1-81.6
- mean: 64.7 73.2
- standard deviation: 2.3 5.9



The results of the study are presented in the Table 2. It is found that the regression slope for daughter's longevity as a function of paternal age at reproduction is negative (-0.16 +/- 0.07) and this inverse relationship is statistically significant (Student test is -2.35, P=0.02) even when the effects of other important 4 covariates are taken into account. In the case of sons the association with paternal age at reproduction is much weaker (-0.06 +/- 0.05) and statistically insignificant (Student test is -1.20, P=0.23). Thus, this study reconfirms the previous preliminary observations [1,2] on the sex-specific life-shortening effect of late paternal reproduction on daughters' longevity and provides strong scientific evidence in favour of these observations. It is important now to continue these studies further and to check the prediction of the X chromosome hypothesis - the expected specific life-shortening effect of late grandpaternal reproduction from mother's side only.

Table 2. Parental Predictors of Human Longevity. Coefficients (slopes) of multiple linear regression +/- standard error.

Variable Sons Daughters
Paternal age at reproduction -0.06 +/- 0.05 -0.16 +/- 0.07
Maternal age at reproduction 0.03 +/- 0.04 0.02 +/- 0.06
Paternal age at death 0.13 +/- 0.02 0.09 +/- 0.03
Maternal age at death 0.03 +/- 0.01 0.04 +/- 0.02
Cohort life expectancy 1.07 +/- 0.10 1.04 +/- 0.05
Other characteristics of regression:
Multiple R 0.2 0.4
F Ratio 37.2 86.3



Acknowledgments. This work was supported by the European Community (grant INTAS 93-1617-ext). In order to continue these studies further, we need now additional funding and would greatly appreciate if potential sponsors contact us by E-mail <leonid@gavrilov.genebee.msu.su> or by fax: 7-095-939-0338/3181.



References



1. Gavrilov L.A., Gavrilova N.S. (1997). Parental age at conception and offspring longevity. Reviews in Clinical Gerontology, 7, 5-12.

2. Gavrilov L.A., Gavrilova N.S., Kroutko V.N. et al. (1997). Mutation load and human longevity. Mutation Research, 375 61-62.

3. Vijg J., Gossen J.A. (1993). Somatic mutations and cellular aging. Comp.Biochem.Physiol., 104B, 3, 429-437.

4. Crow J. (1993). How much do we know about spontaneous human mutation rates? Environ.Mol.Mutagenesis, 21, 122-129.

5. Crow J. (1995). Spontaneous mutation as a risk factor. Exp.Clin. Immunogenet., 12, 121-128.

6. Genealogisches Handbuch des Adels. (Van Hueck W., ed.). C.A.Starke Verlag, Limburg an der Lahn (1994) 107, 106; Ibid. (1993) 105, 104; Ibid. (1992) 103, 102; Ibid. (1991) 101, 100; Ibid. (1988) 93; Ibid. (1987) 92, 90; Ibid. (1986) 89, 88; Ibid. (1985) 87, 86; Ibid. (1980) 75.

7. Gavrilov L.A., Gavrilova N.S., Evdokushkina G.N. et al. (1996). Determinants of human longevity: parental age at reproduction and offspring longevity. Longevity Rep., 10(54), 7-15.


Comparison of Maternal and Paternal Effects

on Human Longevity

by Leonid A.Gavrilov, Natalia S.Gavrilova, Galina N.Evdokushkina, Victoria G.Semyonova, Anna L.Gavrilova, Natalia N.Evdokushkina, Yulia E.Kushnareva, Alexander Yu.Andreyev, Vyacheslav N.Kroutko A.N.Belozersky Institute, Moscow State University, Moscow, Russia (electronic mail: leonid@gavrilov.genebee.msu.su) and Institute for Systems Analysis, Russian Academy of Sciences, Moscow, Russia (electronic mail: gavrilov@glas.apc.org). Copyright - L.A.Gavrilov



In order to understand the mechanisms of human longevity it is important to know the type of its inheritance. For example, specific transmission of human longevity from father to son only might indicate that human longevity genes are located in Y chromosome. In the case of specific transmission of human longevity from father to daughter only, one may suggest that longevity genes are located in X chromosome since only daughters inherit this chromosome from the father. Strong maternal effect for inheritance of human longevity might indicate the involvement of mitochondrial DNA, since it is inherited from maternal side only. Thus, it is very important to find out what is the relative contribution of maternal and paternal longevity into sons' and daughters' life span and to compare these observations with different models and hypotheses of longevity inheritance.



The purpose of this particular work is to study the above mentioned problem. Special attention was paid to the quality of data used in this study. For this purpose we have collected, computerized and analyzed the most reliable genealogical data on human longevity in more than 700 different European royal and noble families published in the famous edition Genealogisches Handbuch des Adels1-4 and in other 120 professional genealogical sources, listed elsewhere5. In particular, the data on royal, tsar and prince families was taken from the Genealogisches Handbuch der Furstlichen Hauser1. The data on count (earl) nobility families was taken from the Genealogisches Handbuch der Graflichen Hauser2, on baronial nobility families - from the Genealogisches Handbuch der Freiherrlinhen Hauser3 and on gentry (non-titled noble) families - from the Genealogisches Handbuch der Adeligen Hauser4.



Offspring life span was analyzed for adult sons and daughters (those who survived by age 30) in order to eliminate effects of high infant mortality and high proportion of violent deaths at young ages. The data for offspring born after 1880 was excluded from the analysis in order to have unbiased estimates of longevity for extinct birth cohorts. The data for offspring born before 19th century was also excluded in order to minimize the heterogeneity of the sample. For each birth cohort the mean sex-specific expectation of life at age 30 was calculated and used as an independent variable in multiple linear regression to control for cohort and secular trends and fluctuations in human longevity. Offspring longevity for each particular sex (6264 records for males and 2285 records for females) was considered as a dependent variable in multiple linear regression model (program 1R in BMDP statistical package) and a function of 3 independent predictors: paternal age at death, maternal age at death and sex-specific cohort life expectancy. The data analysis was made for different ranges of parental (both paternal and maternal) ages at death: 30-110, 40-110, 50-110, 60-110 and 70-110 years.



The results of this study for sons' longevity are presented in Table 1. Both paternal and maternal longevity has positive statistically significant effect on longevity of sons. The effect is higher for longer lived parents, especially in the case of fathers. The paternal effect (slope coefficient of multiple regression model) is higher than maternal effect at any level of parental longevity and in most cases this difference is statistically significant (Table 1).
Table 1. Sons' longevity as a function of paternal and maternal life span. Parameters of the multiple linear regression model.
Parental Number of Linear regression slopes Difference between
age at cases in +/- standard error paternal and maternal
death regression Paternal Maternal effects
(range)   effect effect +/- standard error
30-110 6264 0.097 +/- 0.014 0.039 +/- 0.012 0.058 +/- 0.018**
40-110 5686 0.109 +/- 0.016 0.049 +/- 0.015 0.060 +/- 0.022**
50-110 4752 0.125 +/- 0.020 0.064 +/- 0.020 0.061 +/- 0.028*
60-110 3415 0.143 +/- 0.030 0.079 +/- 0.030 0.064 +/- 0.043
70-110 1627 0.191 +/- 0.060 0.018 +/- 0.059 0.173 +/- 0.084*
Difference between paternal and maternal effects is statistically significant at 0.05 level.
** - Difference between paternal and maternal effects is statistically significant at 0.01 level.







The effects of parental longevity on daughters are presented in Table 2. Both paternal and maternal life span are positive predictors of daughters' longevity and paternal effects are especially high in the case of longer lived parents. In all cases the paternal effects seems to be higher than maternal ones, although the sample size should be increased in further studies in order to check the statistical significance of this observation more carefully (Table 2).
Table 2. Daughters' longevity as a function of paternal and maternal life span. Parameters of the multiple linear regression model.
Parental Number of Linear regression slopes Difference between
age at cases in +/- standard error paternal and maternal
death regression Paternal Maternal effects
(range)   effect effect +/- standard error
30-110 2285 0.061 +/- 0.024 0.019 +/- 0.020 0.042 +/- 0.031
40-110 2045 0.078 +/- 0.028 0.046 +/- 0.025 0.032 +/- 0.038
50-110 1677 0.129 +/- 0.036 0.101 +/- 0.034 0.028 +/- 0.050
60-110 1195 0.206 +/- 0.053 0.116 +/- 0.052 0.090 +/- 0.074
70-110 588 0.367 +/- 0.098 0.080 +/- 0.100 0.287 +/- 0.140*
* - Difference between paternal and maternal effects is statistically significant at 0.05 level.







The most interesting result of this study is that the maternal longevity effect does not exceed the paternal one - in fact the opposite tendency is observed. This observation is surprising since mother has many different additional influences on the offspring through specific inheritance of mitochondrial DNA, strong maternal-child interaction during in utero development and later during the formative years of the child. For this reason the maternal effect on offspring traits is usually higher than the paternal one [6]. It is interesting that human longevity is an exception from this common observation and in fact the paternal effects tend even to exceed the maternal ones.



In order to explain the paradoxically stronger paternal effect on human longevity, we suggest the following hypothesis. In the case of mothers all recessive mutations could affect their longevity in those rare cases only when they are in homozygous form. That is why the long-lived mothers may carry essentially the same mutation load as the short-lived mothers and the only difference for long-lived mothers might be more heterozygous pattern for their mutation load. On the other hand in the case of fathers any mutations affecting longevity could not be compensated (complemented by other alleles) if they are located on X or Y chromosome. Thus, the relationship between genes and phenotypic longevity should be more straightforward and simple for fathers than for mothers. That is why the paternal longevity might be a better predictor for offspring longevity than the maternal one. According to our suggested explanation, the stronger paternal longevity effect is related to male hemizygosity of genes on sex chromosomes and their higher selection in males. There is one interesting prediction from this hypothesis that should be checked in future studies - in families having centenarian grandfather from maternal side (transmission of X chromosome) both daughters and sons could live longer while in families with centenarian grandfather from paternal side (transmission of Y chromosome) the sons should have more "familial longevity benefits" than the daughters. Acknowledgments. This work was supported by the European Community (grant INTAS 93-1617-ext). In order to continue these studies further, we need now additional funding and would greatly appreciate if potential sponsors contact us by E-mail <leonid@gavrilov.genebee.msu.su> or by fax: 7-095-939-0338/3181.



References



1. Genealogisches Handbuch des Adels. Genealogisches Handbuch der Furstlichen Hauser(Van Hueck W., ed.). C.A.Starke Verlag, Limburg an der Lahn (1991) 100; Ibid. (1987) 90; Ibid. (1984) 85; Ibid. (1980) 75.

2. Genealogisches Handbuch des Adels. Genealogisches Handbuch der Graflichen Hauser (Van Hueck W., ed.). C.A.Starke Verlag, Limburg an der Lahn (1993) 105, 104; Ibid. (1991) 101; Ibid. (1983) 82.

3. Genealogisches Handbuch des Adels. Genealogisches Handbuch der Freicherrlinhen Hauser(Van Hueck W., ed.). C.A.Starke Verlag, Limburg an der Lahn (1994) 107, 106; Ibid. (1992) 102; Ibid. (1986) 88.

4. Genealogisches Handbuch des Adels. Genealogisches Handbuch der Adeligen Hauser (Van Hueck W., ed.). C.A.Starke Verlag, Limburg an der Lahn (1992) 103; Ibid. (1988) 93; Ibid. (1987) 92; Ibid. (1986) 89; Ibid. (1985) 87, 86; Ibid. (1984) 83; Ibid. (1983) 81;

5. Gavrilov L.A., Gavrilova N.S., Evdokushkina G.N. et al. (1996). Determinants of human longevity: parental age at reproduction and offspring longevity. Longevity Rep., 10(54), 7-15.

6. Falconer D.S. (1981). Introduction to Quantitative Genetics (2nd edition). Longman, London and New York.


Letter

From Mr E. P. Suter (Switzerland)



re Cryonics: I think it will be sooner or later unnecessary when someone finds the gene which is responsible for getting older. Taking it out would mean that you can live for hundred of years in the same shape - Poor world!



Comment



Every aspect of the human body is subject to disease. There are many genetic diseases, such as sickle cell anaemia.



It is observed that some people are not affected by certain carcinogens, such as tobacco smoke. One of the reasons for this is that they have a gene that prevents cancer. Others have a "disease" namely the absence of this gene, and they die as a result of smoking their lungs with tobacco smoke.



If an ageing gene, without which we would not age, existed, there would be some disease that would stop it working. People "suffering" from this disease would not grow old. We do not observe a small number of people never growing old. Therefore there is no ageing gene.



What may be possible is that we can modify many genes to the effect that we can live longer. This would be a process similar to taking vitamins. Ensuring that everyone has anti-cancer genes, for example, by adding them to people using genetic therapy will enable these people so treated to die of something other than cancer, but they will still die. Many common causes of death can be eliminated this way, and it will be common for people to live longer and longer. The weakening effects of ageing can be reversed, but there will be an increasing problem of side effects to all these therapies.



Ultimately ageing will only be abolished by a re-design of the human body, not in shape or appearance but in working processes. Our present level of understanding of the building blocks of life suggest to me that such a re-design is still decades or more like centuries from the present date. Cryopreservation will enable people who were born too soon to benefit from all this progress. It can be regarded as an ambulance moving people through time to where they can be cured. We do not restrict medical treatment to those who can get to the surgery under their own power. We allow ambulances (and other vehicles) to taken them across greater distances to get there. Why should we not allow a process that gets people across time to a cure? Sure, the journey though time is risky, but we don't let people die because there is a risk the ambulance may break down, catch fire or be crushed by a heavy lorry on the way to hospital.



The other weak point in your argument is in the comment "Poor World". Why does it matter which particular people occupy it? Those alive now living forever or a self replicating chain of different people? If the idea that each individual should die to make room for someone else was taken to the logical limit, everyone will kill themselves as soon as they hear of it and there will be no one left.



Also, of course, the comment "Poor World" suggests that the world is the only space that humans can occupy. The universe, as far as we can observe it, appears to be empty of life. Certainly the solar system is empty.

Fruit Fly Experiments



by Douglas Skrecky



Sixth Update



This is the sixth update on my fly experiments. On day 77 all flies from the first run had expired. The two modest winners were forskolin and NADH. Since there was no control bottle it is not certain that either of these was actually increasing life span.

First Run
  Survival
Supplement DAY 21 DAY 31 DAY 43 DAY 56 DAY 67 DAY 77
alpha lipoic 45% 22% 11% 0% 0% 0%
Biotin 38 12 0 0 0 0
CLA 43 0 0 0 0 0
Forskolin 90 80 80 50 10 0
Glutamine 100 17 17 17 0 0
Lycopene 100 100 60 20 0 0
NADH 86 86 86 57 14 0
Pregnenolone 100 75 37 12 0 0
Pyroglutaminc 62 5 0 25 12 0
RNA 57 0 0 0 0 0
Xanthophyll 62 75 25 12 12 0




During the day 21 census for the second run I found one extra fly each in the acetylcarnitine and clove bottles. Hopefully all the flies in the bottles have now been discovered.



One remarkable finding is that there was no additional mortality in the control, nicotinamide, coenzyme Q10, basil, chlorophyll, cloves, dextromethorphan, fenugreek, leucoanthocyanin and rosemary bottles. This tends to support my hunch that pathogens were causing the early mortality. Since the bottles in this run are newer, they are probably cleaner than the breeding bottles the flies were derived from. I was originally going to start some more breeding bottles and adding thyme to help keep the bacteria under control. However since I did not know anything about the long term toxicity of thyme I decided to delay starting more breeding bottles until a second census had been completed. I think the significant decrease in survival in the cumin (100% to 57%), oregano (88% to 50%), caraway (67% to 33%) and ginger (67% to 17%) bottles may reflect a direct toxic action of these spices. Only the coenzyme Q10 and chlorophyll bottles are now maintaining 100% survival.
Second Run
  Survival
Supplement DAY 11 DAY 21
Control 63% 63%
Nicotinamide 86 86
Coenzyme Q10 100 100
Nicotinamide/CoQ10 86 57
Acetylcarnitine 86 63
ALC/COQ10 100 86
Basil 80 80
Bromelain 78 67
Caraway 67 33
Chlorophyll 100 100
Cloves 83 86
Cumin 100 57
Curcumin 71 57
Dextromethorphan 83 83
Fenugreek 80 80
Ginger 67 17
Green Tea 100 83
Leucoanthocyanins 86 86
Mace 71 57
Nutmeg 71 57
Oregano 88 50
Rosemary 90 90
Sage 100 75
Thyme 100 88





Seventh Update



This is the seventh update on my fly experiments. There no longer exist any bottles maintaining 100% survival. Neglecting the mortality which occurred before the day 11 census, only the nicotinamide and basil bottles have avoided further attrition. The highest survival is now the nicotinamide bottle at 86%, followed by basil at 80% and sage at 75%.
Second Run
  Survival
Supplement DAY 11 DAY 21 DAY 31
Control 63% 63% 38%
Nicotinamide 86 86 86
Coenzyme Q10 100 100 57
Nicotinamide/CoQ10 86 57 29
Acetylcarnitine 86 63 38
ALC/COQ10 100 86 43
Basil 80 80 80
Bromelain 78 67 56
Caraway 67 33 17
Chlorophyll 100 100 67
Cloves 83 86 57
Cumin 100 57 71
Curcumin 71 57 29
Dextromethorphan 83 83 67
Fenugreek 80 80 40
Ginger 67 17 0
Green Tea 100 83 67
Leucoanthocyanins 86 86 57
Mace 71 57 29
Nutmeg 71 57 57
Oregano 88 50 25
Rosemary 90 90 64
Sage 100 75 75
Thyme 100 88 25





The high recent attrition in the thyme bottle might not be due to either aging, disease or any deleterious effect of thyme. Unfortunately the fly food at the bottom of the thyme bottle has dried out a bit and pulled away from the bottle, leaving a narrow crack where all of the new fly corpses were found. When I start my third run I will be adding a bit more water to the fly food so as to prevent this. This "crack trapping" of flies might also account for the recent deaths in the rosemary bottle as well.



I have started several new breeding bottles with added thyme to act as a bactericide. The old breeding bottles initially were plugged by cotton, before I replaced these with cardboard. It is possible that bacteria might have been admitted through the cotton. The new breeding bottles were prepared under reasonably clean conditions. All bottles I use are first heated in an oven to sterilize them and the tools used to prepare the fly food are all washed with alcohol beforehand.



One of the dead flies in the day 21 census in the cumin bottle has done a lazarus and come back to life. I try to shake the bottles to see if any flies are playing possum, but this does not always work.



One of the flies in the chlorophyll bottle has disappeared! There is so much chlorophyll in this bottle that the fly food appears black rather than green and it is very hard to spot the little buggers. I tried my best but only 6 of the 7 flies originally in the bottle were visible.



All the flies in the ginger bottle are now dead. I suspect they died of toxic effects associated with either a ginger overdose or perhaps due to aflatoxin contamination.



I find it difficult to even speculate why the combination of nicotinamide and coenzyme Q10 resulted in a lower survival than either supplement taken individually. Perhaps the 7 flies in this bottle were just "unlucky". The fact I am using small numbers of flies means some bottles statistically are going to underperform for no reason at all. Only the law of large numbers can cure this problem, but if I use 100 flies to screen each supplement this experiment will grind to a halt. The nicotinamde bottle now maintains the highest survival with 6 alive and only 1 dead. Only time will tell whether either nicotinamide, basil or any other supplement will significantly outperform the controls in the long run. In any case before one can believe any good results, replications using larger numbers of flies will be necessary.



In a philosophical moment I had been speculating why longevity experiments using flies have not been done testing the effect of thousands of supplements already. It is not like it is a lot of trouble. The local fly lab that I got my flies from probably has millions of flies in bottles. Every large university on this continent has a fly lab with similar capabilities. It would take only a trivial fraction of these resources to crack open the mechanisms of fly (if not human) aging by a brute force approach. Why hasn't it happened?



Whatever the reason, I intend to continue plugging away until I have at least doubled fly life spans. If necessary I'll test hundreds of supplements myself to achieve this.



Eighth update



This is the eighth update on my fly experiments. The highest survival is now in the sage bottle (62%). followed by cumin & nicotinamide at 43% and basil at 40%. With a 25% survival the control bottle is now doing better than many others. The high attrition between the day 31 and 42 census I attribute mostly to aging. The flies for this run were derived from old breeding bottles, which were originally started on February 5'th. Since this run was started on March 24'th, some of the flies may have been already middle aged by then. For an explanation of the bracketed numbers please refer to the text below.
Second Run
  Survival
Supplement DAY 11 DAY 21 DAY 31 DAY 42
Control 63% 63% 38% 25%(38%)
Nicotinamide 86 86 86 43 (86)
Coenzyme Q10 100 100 57 0
Nicotinamide/CoQ10 86 57 29 0
Acetylcarnitine 86 63 38 12
ALC/COQ10 100 86 43 14
Basil 80 80 80 40 (80)
Bromelain 78 67 56 11
Caraway 67 33 17 17
Chlorophyll 100 100 67 14 (67)
Cloves 83 86 57 0
Cumin 100 57 71 43 (50)
Curcumin 71 57 29 14
Dextromethorphan 83 83 67 33
Fenugreek 80 80 40 20 (60)
Ginger 67 17 0 0
Green Tea 100 83 67 33
Leucoanthocyanins 86 86 57 14
Mace 71 57 29 0
Nutmeg 71 57 57 29 (57)
Oregano 88 50 25 0
Rosemary 90 90 64 10 (70)
Sage 100 75 75 62
Thyme 100 88 25 12 (62)



One major defect in this run is a phenomenum I call crack trapping. This occurs because I added less water to the fly food than during the first run. When the food further dries it pulls away from the side of the bottle and opens up a narrow crevasse or crack that flies seem to get trapped in and then die. I do not know whether these would have died or not if more water had been added, so to document this uncertainty I have indicated what the survival would be if all trapped flies were regarded as being still alive. The adjusted survival figure is given in brackets. In many bottles no flies were trapped, but in the basil, chlorophyll, fenugreek, nicotinamide, rosemary & thyme bottles this is a major confounding variable.



The reason this happened was due to my following the instructions on the fly food package - silly me. This recommended that equal volumes of 4-24 medium and water be added together, which is what I did in the first run, where no crack trapping occurred. However it also advised that in large bottles, with larger amounts of medium being used, that less water be used. I discovered the reason for this addendum the hard way. Adding too much water to breeding bottles results in flies drowning as pools of water form after a lot of breeding has occurred and used up much of the medium. It seems that flies themselves have a smaller percentage water than that in the medium. This worry does not apply to my life span test bottles, since enough taurine larvicide is added to prevent any breeding. The moral seems to be to add less water to breeding bottles, but continue using a 1-to-1 food/water volume ratio for test bottles. Live and learn.



Ninth Update



This is the ninth update on my fly experiments. Just the control, nicotinamide and chlorophyll bottles have one fly each left alive in them. The sage bottle has two left and all the other bottles have none. The fact that the control bottle now has one of the highest survival rates is an event which needs an explanation! I think I may have found one. Unlike mammals, flies experience a greatly accelerated mortality when they are fed fats. (Exp. Geront. 14:95-100 1979) Since most spices contain some fat, it can be expected that many of them will decrease fly longevity.

Second Run Survival
Supplement DAY 11 DAY 21 DAY 31 DAY 42 DAY 53
Control 63% 63% 38% 25% 12%
Nicotinamide 86 86 86 43 14
Coenzyme Q10 100 100 57 0 0
Nicotinamide/CoQ10 86 57 29 0 0
Acetylcarnitine 86 63 38 12 0
ALC/COQ10 100 86 43 14 0
Basil 80 80 80 40 0
Bromelain 78 67 56 11 0
Caraway 67 33 17 17 0
Chlorophyll 100 100 67 14 14
Cloves 83 86 57 0 0
Cumin 100 57 71 43 0
Curcumin 71 57 29 14 0
Dextromethorphan 83 83 67 33 0
Fenugreek 80 80 40 20 0
Ginger 67 17 0 0 0
Green Tea 100 83 67 33 0
Leucoanthocyanins 86 86 57 14 0
Mace 71 57 29 0 0
Nutmeg 71 57 57 29 0
Oregano 88 50 25 0 0
Rosemary 90 90 64 10 0
Sage 100 75 75 62 25
Thyme 100 88 25 12 0






I have started the third run, which is as follows:
Supplement concentration (mg/100 ml)
Control
Activated charcoal 87
Amchoor 500
Angelica 500
Anise 500
Bay 500
Beet 500
Betaine HCL 165
Carrot 500
Celery seed 500
Citrus bioflavonoids 215
Comfrey 500
Dill seed 500
Green pea 500
Hydroxycitric acid 83
Kelp 500
Malt 500
Melatonin 1.3
Melatonin 2X 2.6
Melatonin 4X 5.2
Nicotinamide 500
Paprika 500
Para-aminobenzoic acid 165
Purple yam 500
Rosehip 500
Sage 500
Sage 2X 1000
Sage 4X 2000
Silica 37
Spinach 500
Tumerin ?



Since sage was the "first place finisher" in the second run, I am taking a more detailed look at this spice in the third run. Nicotinamide also looked promising, but the dosage may have been too low in the second run for a significant benefit to be obtained. I will see if a high dosage of nicotinamide is more helpful in the third run.



Low doses of melatonin have modestly extended maximum life span in rodents. However in the May 1997 issue of Life Extension Magazine it was reported that Dr. Roman Rozencwaig doubled the life span of rotifiers by giving them melatonin. Could this be because he used a lot of melatonin? Could high dose melatonin double rodent life span? I will examine the dose/reponse effect of melatonin on flies.



The most powerful DNA protecting antioxidant in existence is called tumerin, which forms 0.1% of the dry weight of the spice tumeric. (Archives of Biochemistry and Biophysics 292(2): 617-623 1992) Since tumerin is heat stable and water soluble I boiled some tumeric in water, let it settle and then poured off the water. This water extract should hold most of the tumerin, but relatively little of the curcumin, which gives tumeric its yellow colour. Unfortunately a negative result with tumerin will not mean that accumulating DNA damage has little effect on fly longevity, since tumerin is a high molecular weight antioxidant (5000 daltons) and might not be absorbed by the flies. Still it is worth a try.



Tenth Update



This is the tenth update on my fly experiments. All the flies from the second run are dead. The results are as follows:

Second Run Survival
Supplement DAY 11 DAY 21 DAY 31 DAY 42 DAY 53 DAY 64
Control 63% 63% 38% 25% 12% 0
Nicotinamide 86 86 86 43 14 0
Coenzyme Q10 100 100 57 0 0 0
Nicotinamide/CoQ10 86 57 29 0 0 0
Acetylcarnitine 86 63 38 12 0 0
ALC/COQ10 100 86 43 14 0 0
Basil 80 80 80 40 0 0
Bromelain 78 67 56 11 0 0
Caraway 67 33 17 17 0 0
Chlorophyll 100 100 67 14 14 0
Cloves 83 86 57 0 0 0
Cumin 100 57 71 43 0 0
Curcumin 71 57 29 14 0 0
Dextromethorphan 83 83 67 33 0 0
Fenugreek 80 80 40 20 0 0
Ginger 67 17 0 0 0 0
Green Tea 100 83 67 33 0 0
Leucoanthocyanins 86 86 57 14 0 0
Mace 71 57 29 0 0 0
Nutmeg 71 57 57 29 0 0
Oregano 88 50 25 0 0 0
Rosemary 90 90 64 10 0 0
Sage 100 75 75 62 25 0
Thyme 100 88 25 12 0 0




Overall I wasn't too impressed by any of the supplements tested during the second run. Although sage, followed by nicotinamide and chlorophyll look a little interesting, the increased survivals may merely be an artifact of a decrease in early mortality and may not be due to any antiaging effect. I'm taking a look at higher dosages of sage and nicotinamde in the third run. The preliminary results for this are as follows:
Third Run Day 17 Census
Supplement #Alive #Dead %Survival
Control 9 5 64%
Activated charcoal 20 3 87
Amchoor 8 3 73
Angelica 19 15 56
Anise 5 6 45
Bay 9 4 69
Beet 5 3 62
Betaine HCL 9 2 82
Carrot 4 6 40
Celery seed 9 1 90
Citrus bioflavonoids 13 7 65
Comfrey 7 1 88
Dill seed 9 2 82
Green pea 25 8 76
Hydroxycitric acid 7 8 47
Kelp 9 5 64
Malt 30 6 83
Melatonin 7 6 54
Melatonin 2X 12 5 70
Melatonin 4X 13 7 65
Nicotinamide 6X 4 10 28
Paprika 9 4 69
Para-aminobenzoic acid 14 3 82
Purple yam 11 1 92
Rosehip 15 2 88
Sage 19 10 66
Sage 2X 12 6 67
Sage 4X 15 1 94
Silica 14 2 88
Spinach 2 3 40
Tumerin 16 3 84





Although the breeding bottles used for the third run contained some thyme to help act as a bactericide, this apparently was not enough to prevent a lot of early mortality in the third run. I will have to use a better bactericide for the breeding bottles I will use for the fourth run.



It is too early to tell if any supplement is exerting any antiaging effect. However it does appear that a dosage of nicotinamide six times as high as that used in the second run is toxic. At just 28% the nicotinamde bottle has the lowest survival. This reminds me of the results obtained long ago with vitamin B5, where a low dosage increased survival and a high dosage decreased it. I wonder whether excessive dosing with vitamins was a factor in making Durk Pearson look older than he is. It is possible that this famous life extensionist has indeed succeeded in altering his rate of aging, just that it is unfortunately an increase rather than a decrease in the rate.



This run I used more flies for most bottles than in previous runs. However whenever the number of flies in a bottle rose above 20, I found I nearly had to go cross-eyed to count all these flies as they moved around. In future I will keep the numbers always below 20.


As others see us:



New Hope International:



Longevity Report (West Towan House, Porthtowan, Truro TR4 8AX) A collection of scientific or pseudo- scientific articles, most of them advocating the use of cryonics or, in layperson's terms, the freezing of human corpses so that at some future time the person can be brought back by improved technology. I don't really sense there is a debate going on here. The contributors are united in the belief that this would be a good thing. There is an article on the British Columbia Cemetery and Funeral Services Act. another on Deprenyl and Life Extension.



The tone is very much that of preaching to the converted. "The revolution which we can create will last forever", proclaims one writer. That's exactly what bothers me. Surely there are enough human beingson the planet with- out resurrecting cIapped-out ones? And surely the resources available to us should be spent in a way likely to benefit the many rather than the few? Call me an old Bentharnite if you will, I couldn't get into this. The article Atheists Discuss Death sounded interesting, but failed to deliver. I would quibble with its assertion that most atheists believe in capital punishment. In fact I'd quibble with quite a few sweeping generalisations in here. To give him his due, the editor does make it clear that he doesn't necessarily agree with everything that appears. (Sheila Hamilton)



New Hope International, 20, Wenerth Avenue, Gee Cross, Hude, SK14 5NL, UK. 15 for six issues (20 outside UK) All cheques payable to "Gerald England" please. No non-sterling cheques. Overseas pay cash or international giro.



Microtech Or Nanotech ?

by Yvan Bozzonetti



There is two paths on the way towards nanotechnology: The up down and the down up. The up down starts with macroscopic devices and try to reduce them, this is the Merlin wizard way of working. Merlin's followers are mostly found in the electronics industry and what they want to do is using photolithography developed for micro chips to make micro-mechanical devices. They have encountered some technological success, today, nearly everything we can found in mechanics can be reduced at the micron scale or near that level. The big problem is to find a market for that technology. Up to now, predictions have been numerous in the field but there remains few realizations.



Today, micro-technology remains confined in the realm of captors and detectors. This is interesting and important but there is no mass market. On the other side, electronics products thrive on an enormous potential selling at least some million of units for each component. The trouble with micro-technology is not the technology itself, it is its market. In fact these products have not found their market up to now!



The down up approach starts with quantum scale components such atoms and small molecules and try to build more advanced systems. Chemistry and biotechnology are the starting ground in that domain. Chemistry can produce elementary components such flywheels, cables, tubes... Biological systems are more advanced, for example some protein complexes called chaperones can cast a given polypeptide in a given form with a given reactivity or function. this is the most advanced system we can use at nanotech level. All of that is in the classical domain, even if chemical scale is in fact a quantum system in disguise. Recently, a new level has surfaced: the smart matter, a concept coming from quantum computer thinking. There is no realization and even no proposal for a realization of smart matter system. If we take a pragmatic slant, we are facing four steps in the nanotech world: - For microtech, everything is done at the fundamental level, what we need is "simply" a market. -For bio components, we must identify what we can found in the natural world, adapt them to our needs and extrapolate to new functions. -Chemistry is the basic ground for doing anything we can want at nanoscale, the only problem is: it is a dream domain full of Drexler promise but with few hard facts. -Smart matter is not on the practical agenda for some time, even if state superposition, de-localization, void cooling, quantum non-demolition and other quantum tricks go well beyond any honest nanotech buff can dream.



If we wan the best impact in the shortest time, what we have seen let few option: We must concentrate on the up down technology, not to do researches on some ill defined subject but to find a proper mass market. Here, I want to make two proposals, both in the computer domain. The first has to do with DNA computers and the second with nuclear magnetic resonance quantum computing, seen as an extension of the first idea.



The DNA computers (there are many proposals to implement that technology) start with a simple idea: DNA contains a double binary code produced by the elementary nucleotides Adenine (A) thymine (T) cytosine (C) and guanine (G). On the DNA double strand, A sticks to T and C to G. So we can for example select T and G for 0 and 1 in a binary code. If we copy that code on a second DNA strand we get A and C. So, T = A = 0 and G = C = 1, if we have a molecule such: ATGGC, we can read it as 11000 or 24 written in binary code. Now, if that molecule is eroded to TGGC, 24 becomes 8, this may be interesting to do computations, but if the action is not intended, there is a important error. Each bit of information must then be coded on more than one DNA bit so that DNA gives two lots of information: the bit value and its position in the number.



For example if we do computations on 64 bit-numbers, then each bit of information must be defined by seven DNA nucleotides. That gives 2^7 = 128 possibilities or 0 or 1 on any of the 64 allowed slots. A number is so build from a DNA stretch 448 nucleotides long. I don't want to go there in the intricacies of DNA computing and how each elementary logic or mathematic function is implemented. It suffice to say every function has been reproduced in that system. Our objective here is not to make some new invention, simply to find a market for micro-technology.



What is interesting with DNA is the number of molecules implied in a computation round. Each molecule can figure out a different number. With 64 bits, there may be up to some 10^18 molecules. If a computation run takes 20 minutes or near 1 000 seconds, the computer power is near one petaflop, 1 000 times the power of the most powerful present day supercomputer. Today, we can handle DNA stretches near 10 000 nucleotides long, giving 1024 bit-numbers. This is too much to exploit every possible molecule. On the other hand, computations could be done on a basis larger than two; Another possibility would be to use the position coded bits to figure transfinite numbers first explored by Georg Cantor. The simplest mathematical field using transfinites was named ON2 by the Cambridge mathematician John H. Conway. ON2 has many built in simplifications to do quantum computing. A DNA computer could then simulate a quantum system or a quantum computer in some limits.



The big drawback of a DNA computer today is the enormous mass of pipes, pumps, biological reactors needed to implement it. This approach is as building an electronics computer from valve tubes. What I suggest is to use micromechanics to build a DNA computer on a chip. In fact, we don't need the high tech systems used in electronics to build such a computer, second hand systems used in the printing industry would fit the bill. Indeed, more we want computing power, more we must use long numbers and more DNA molecules we must process. If we work with 64 bits and one quintillon molecules, then we must have a micron scale technology. With 128 bits and a potential for more molecules than we can handle, sub-millimetre etching of plastic plates is more than sufficient. Twenty years ago, I have seen such plates produced for computation with fluid dynamics. Today, the same technology could process 10^20 molecules in a single computing round producing a 100 petaflops computer for less than $ 10 000 with the photolitography technology. For a large production, casting would bring back price under $ 1 000 in the personal computer range.



Everything in that technology may be done on the net, each function implemented using electronics designing softwares build for microchips making. Then, any typographic printer could make the photo-lithographic work.



Now, there is a problem I have not bothered about until now, it is how to read results of a computation at the end of a run. Yes, we can analyse each DNA molecule after amplification by the polymerase chain reaction. The old radio-active labelling produce a result after some months! The new fluorescent dye method looks faster with results in the hour. This is quite workable for a research system. For more wide spread use, a new interface must be built, using nuclear magnetic resonance analysis.



In that technology, a continuous magnetic field generates a privileged direction for half integer spin nucleus such the hydrogen one. A spin 1/2 quantum object has two classical states: up and down, the magnetic field discriminates between them, producing a slightly lower energy for the up state. Many atom decay then at that state. If a radio pulse giving the energy difference between up and down is applied, some up atom will absorb a radio frequency photon and switch to down state. When the radio generator is cut off, these atoms give back the radio energy after a while and return to the up state. The absorbed and remitted energy is defined by the continuous magnetic field power seen by the nucleus. That magnetic field is the sum of the applied exterior field and a local field generated by nearby atoms. The trick is then to produce a wide band radio emission to pump in the high energy state all atoms, whatever the local field they undergo and watch out the frequencies produced after the radio generator has stopped. From the radio spectral lines recovered, we can find back what was the local fields and so produce an analysis of the molecules. Such a system works in seconds or less, it is the most interesting device to adapt to a DNA computer to read off its answers.



Now there is a trick: Assume there is only one molecular kind and we know exactly what is its radio spectrum so there is nothing left to discover. The second trick would to produce a radio spectrum exactly similar at half the frequency and so, half the energy per photon. The result would be strange and impossible in the classical world. At half the energy, the nucleus spin would be flipped half way between up and down state, something impossible in quantum mechanics. In fact the spins would be sent "elsewhere", no more in the up state, not in the down one or halfway between. This strange reality is often a called a superposition of up and down. If up stands for 0 and down for 1, then the "elsewhere state" is 0 and 1 at the same time. The problem of computing with such numbers come from the instability of superposed states. One spin is frail but if there are billions of spins in billions of molecules for the same bit, then we move from the microsecond to twenty minute stability, enough to do very long computations. If a molecule contains 100 hydrogen atoms with 100 specific environments, there will be 100 spikes in the radio spectrum and there as much bits to compute with.



At that level, a quantum computer is not interesting: We have seen before this level of parallel processing in a DNA computer, a much simpler and cheaper system. On the other hand, a nuclear magnetic resonance analyser can eventually discriminates between at least one thousand frequencies. A one kilobit quantum computer would have a processing power in the 10^300 operations per run. This is more than sufficient to simulate all the particles in the observable universe from the big bang up to now and well beyond. In fact, even without a technology revolution, NMR would allows 128 bits words, this gives a processing power in the 100 undecillon flops range, a value interesting to put in perspective. A neuron can be simulated for one second with 10 000 flops, we have near 10^10 neurons and so a brain can be simulated with 10^14 floating point operation per second. With 10^38 operations, we could simulate 10^10 human brains for 10^14 seconds or 3 million of billions of years, 200 000 times the age of the Universe! I am speaking here about a machine well in the technological range of the next twenty years.



Is Ignorant Freedom

A Good Or Bad Thing?



by Brent Allsop



John de Rivaz writing on the Internet, had some great comments:

Most people cut up and burned or rotted are so treated in the belief that God or Jesus or some other religion-figure will take them to heaven. Is that any more sensible than space ships hiding behind comets?



How would the rest of the world react if the cult that is in the news had snatched people from the streets or even from hospitals to impose their procedures? Yet this is what happens then people who want to be suspended are autopsied and burned or rotted by legal force.



Yes, how shamefully deceptive, devilish, and evil it all is. I was raise in the LDS church (The Mormons) and was taught that the Atheists, Humanists... and other "Anti-Christs" were of the devil, and that choosing them was the same as choosing death. In the Book of Mormon, 2 Nephi 2:27 it says:



"they are free to choose liberty and eternal life, through the great Mediator of all men, or to choose captivity and death, according to the captivity and power of the devil; for he seeketh that all men might be miserable like unto himself."



Imagine my horror as I finally realized that, we are indeed free to choose, but the opposite choice is the one that honestly leads to life and death. And that it is apparently only the leaders and pushers of such doctrines that are the real liars that apparently desire that others be dead or miserable like unto themselves.



I guess in another thousand years we'll know for sure who was right, who was wrong, who is alive, and who is dead and in hell or the grave... and miserable.



As it says in Joshua 24:15: "Choose you this day whom ye will serve..." As for me in my house I will choose life.



Is ignorant freedom a good or bad thing? Should we cryonicists more actively cry words of warning and repentance to the sinful liars of the world? Otherwise it's going to be mighty lonely. At least until we, Like Tippler claims, will finally be able to resurrect even the "information theoretically dead, cut up, and rotted souls".



I never much cared for hellfire and damnation doctrines but isn't this fairly close to the way reality is turning out, at least for the cryonicist? The warnings of a cryonicist sure sound a lot more credible and real than the threats of the various Gods to me.

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