April 28, 1999


Georg Duve
Hamburg, GERMANY
E-mail: gduve@t-online.de

Note: Even if you don't read German, you may still wish to visit George's website at www.methusalem.com , since a lot of his material has already been translated into English. By the way, "Methusalem" is the German spelling for the Biblical patriarch we call Methuselah who allegedly lived to age 969. At our suggestion, George has just informed me that clicking on www.methuselah.org now leads one to the very same site. [Note2: the "www.methuselah.com" site had already been taken by another company.]


Early popular theories of aging haven't lead to measurable successes in anti-aging research, as might have been expected, in part because these theories merely described the side effects of aging or other theories like The Free Radical Theory" (popular since 1956 and which has been tested for many years) - still didn't achieve significant results because they didn't have a rigorous theoretical foundation. Of course, many questions posed by these theories still remain unanswered. Nevertheless, I believe it is time to seek a new direction.

In my opinion, we can distinguish at least two approaches to extending the overall healthy human lifespan:

1. Stimulating the replacement of old, mitotically-challenged cells by new ones;

2. Achieving a longer healthy cell life for post-mitotic cells.

For both of these strategies, I believe that new ways of looking at Programmed Cell Death (PCD) and oxygen metabolism are required.

I. Cell Reprogramming and PCD (Steinhardt, AUSTRIA)

Reprogramming the nucleus is sometimes referred to as the "tape recorder" theory. Based on experiments by Prof. Ernst Hadorn of Switzerland Scientific American 1968; National Cancer Institute; 1969], Prof. Leonard Hayflick of the USA, and Prof. John B. Gurdon of the UK [several papers in the 1970's], Martina Steinhardt conducted a number of experiments using the South African frog Xenopus laevis [papers published in both English and German].

Her thesis was that nuclear DNA in the chromosomes, wrapped in histones, can be recorded and played back by specific proteins attached to the DNA. It is suggested that the "biological clock" is not along the DNA string itself but depends on how far the differentiation program of the cell has been executed. The difference between the experiments of Gurdon and Hayflick's cell nuclear transplantations is that the cytoplasm of young fibroblasts is a different 'tape recorder', incapable of playing back the nuclear program while egg protoplasm apparently can do it right. So the DNA is not a string, spliced time after time, but more like a magnetic tape [14]. From the abstract of one of her papers, "These results lead to the conclusion that nuclear transplantation into an enucleated egg yields a 'reprogramming' of the nucleus, including the reprogramming of its replicative capacity as much as the biological age of the nucleus." [1] I am not aware as to whether this experiment was ever followed up. Does anyone know?

II. Oxygen and Free Radicals

Since Dr. Denham Harman first proposed The Free Radical Theory, the role of oxygen has been relegated to more and more of an enemy rather than a life-sustaining element. Several authors have written papers about this ambiguous state-of-affairs [5, 11]. Oxygen is absolutely necessary for cell energy production but with the side effect of having to ameliorate the effects of self-produced free radicals. Despite several papers on the damaging effects of free radicals, there is still no definite result relating to the overall topic - cellular aging. Some long-lived strains of Drosophila show high concentrations of SOD, but there is not yet a coherent picture [5, 8, 11]. Contrary to what one might expect, there is an indication that long-lived species have a lower antioxidant level than short-lived ones [6, 7]. For example, birds have a much higher oxygen consumption and metabolic rate than non-flying animals with same body size [5, 14]. Thus, according to this theory, they should die sooner. However, this does not appear to be the case. On the one hand, this could be the result of a highly effective defense system. But it also could suggest an entirely different view of oxygen itself.

I believe our whole position on oxygen must be revised. Unfortunately, positive papers on the value of oxygen seem to be rare in comparison to papers on the deleterious effects of free radicals. Therefore, the following is only a preliminary view.

We all know that oxygen and H2O2 destroy viruses, bacteria, and other infectious organisms [17]. Also, oxygen is absolutely necessary for energy production. Free Radicals are seen as a byproduct of this process. Cell repair systems are put in place to prolong cell life. But the equation:

"Free Radicals ==> Disease"

is just an assumption. Conversely,

"Disease ==> Free Radicals"

is equally valid [9,10].

It makes more sense to view free radicals as just another front-line immune-system defense. I predict that PCD only occurs whenever a certain threshold is reached. As a result of this process, we should expect to find two biological clocks in place:

  1. Free radicals keep our cells in shape, up to a certain damage level; after that, apoptosis is triggered, followed by cell replacement;
  2. If the free-radical PCD level is never reached, cell life goes on normally within the confines of the Hayflick Limit, which ultimately brings all cell division to an end.

Artificially fighting free radicals with antioxidants may prolong cell life, but ultimately I believe that this will lead to a kind of 'unhealthy' cell which, with age, will start to accumulate pigmented residues and lipid fragments (lipofusin) significantly more than it would have during a normal biological lifetime. As the volume of junk grows within the cytoplasm, it begins to crowd out the functional important machinery of the cell. Maybe there is also a connection between these proposed biological "clocks" and Steinhardt's Theory.

Within the connective tissue of our bodies, mesenchymal stem cells are present and provide a nearly limitless reservoir of fresh cells [4]. With high oxygen levels over the course of the cell's life, mitotic divisions are constantly taking place. This is also the explanation for why several different antioxidation therapies may work: they stimulate the cellular system, respiration (oxygen) and the hematopoietic system, and therefore assists the body in eliminating ineffective cells.

Even Caloric Restriction Theory can be explained in a like manner: Blood flow is vigorous, nutrition optimal, and old cells are destroyed and replaced quickly due to low caloric intake. It has also been established that high body weight reduces oxygen supply. Other body systems, like the Respiratory System for CO2 and acid/base balance are involved. There are indications that chloride ions are adversely related to the blood system [3].

With oxygen being everywhere, why has there been no oxygen-based theory of longevity until now? And what role do mitochondria play? Several systems must be functioning and maintained constantly throughout life. With the need for oxygen, it is just not enough to exercise - one must have correct nutrition, blood flow, body weight, and several other parameters all of which are necessary. And what about living at higher altitudes? Maybe someone has data about the "oxygen status" of Centenarians? The partial pressure of oxygen varies from 90 mmHg at age 30 to only 68 mmHg by age 70 [16]. Typical values for pO2 with age are as follows:

AGE (Years)

PRESSURE (mmHg[Torr])












To achieve a healthy life for our cells, and live longer than the current maximum life span, I believe that it will be necessary to titrate oxygen supplies in every cell to a higher level. Could this be accomplished by introducing oxygen from outside the body or by reducing oxygen's antagonists within? Catalase is present in every cell and constantly refreshed by nutrition (milk products, honey, etc.; in Asia, it must be present in other foods). [2]

Another anti-oxidant enzyme, Glutathione Peroxidase, appears to be solely endogenic and probably could be influenced only partially. However, higher oxygen levels would not result in the end of death! Birds maintain a constantly high level until the end, but nevertheless, the end does come [14]. Therefore, I believe that birds will be a very interesting group in which to search for the ultimate cause(s) of death.

Of course, an extensive literature research has yet to be done. I'm sure that many of these questions could have been answered already simply by a thorough investigation of past work. The entire triggering system for apoptosis and replicative replacement must be scrutinized in detail. How does telomerase play a role? I believe that this approach is far simpler to achieve than searching for means to prolong the life of individual cells.

III. A. Comments on Prof. Michael Fossel's Book Reversing Human Aging [18]

Chapter 1: In the final analysis, "genes are regulated by hormones and other messenger molecules."

Chapter 2: For old cells, death can appear from out of the "clear blue sky." Since even elderly individuals have young stem cells that are perfectly capable of mitosis, shortened telomeres and apoptosis cannot be the sole explanation for collective cell death within a tissue. Where are the "housekeepers" or "gardeners" who are external to the cell?

Chapter 3: Changes to the mantle: What or who regulates the mantle? In the final analysis, cells receives two kinds of signals: (1) growth factors and/or hormones originated by external endocrine tissue and (2) from the chromosomal telomeres themselves. Ultimately, mitosis is carefully regulated by body growth, consistent with tissue architecture, and by contact inhibition from adjacent cells that may be disrupted by trauma, triggering a healing response. Local PCD and the survival of adjacent cells must be exquisitely orchestrated to preserve the underlying architecture of the tissue. When this architecture is obliterated by disease, an inflammatory fibrosis to preserve structural integrity seems to be the only reasonable response.

Even Prof. Fossel hints in his book at the existence of other regulatory mechanisms for mitosis that are independent of the telomere. He sometimes asks why germ cells, in contrast to somatic cells, don't show any sign of aging? Prof. Fossel answers: "Because the telomeres are constantly relengthening stimulated by the presence of the enzyme telomerase." On the other hand, my answer would be: Neither cancer cells nor germ cells age, since they are constantly being rejuvenated by a process of regular mitosis. Aging, as we observe it, only starts when the rapid-proliferative phase of development ends in early adolescence (as explained by Steinhardt). After a period of active proliferation, ova escape from the body by monthly ovulation plus menstruation (or occasionally by birth), while sperm cells continuously divide but later escape from the body by ejaculation. I suspect that cancer cells wouldn't be pathological (by forming tumors) either, were it not for the fact that they aren't regularly expelled from the body. Unhappily, they accumulate in situ . The problem of aging really lies in the lack of a larger "architecture" program in the DNA to maintain a cellular equilibrium of PCD and stem cell proliferation that would preserve the structural integrity of the adult, say, at age 25. Understanding the role of tissue-specific growth factors during embryogenesis and development and their relation to histological architecture is the secret. Wouldn't it be ironic if the key to experimental gerontology lay in experimental embryology?

III. B. Prof. Fossel Responds [April 28, 1999]

The notion that "regular mitosis" extends cellular lifespan is inconsistent with the scientific literature. Cell senescence is correlated with (and experimentally alterable by) telomere length and not with either the number of divisions per se, nor the rate of those divisions, nor the body's capacity for "ejecting" such cells. I appreciate Mr. Duve's comments, but, as far as I am concerned, they are inaccurate. I prefer to rely on data.

[Editor's Comment: If you, yourself, wish to participate in this discussion, please send me E-mail , and your comments will be posted. For your interest, we are planning to introduce a new feature on our website in June for supervised chat rooms on either spontaneous or standard special topics. Supervisors for such discussions are hereby solicited.]

IV. Other Suggestions for Promising Areas of Research

Other interesting areas for aging research might be in the fields of

  1. Cellular Communication [12]
  2. Magnetic/Electrical Fields [15]
  3. Low Gravity Studies [13]
  4. Mutagenesis Resulting from Cosmic Radiation

Were you aware that certain cave-dwelling animals live much longer than their closely-related cousins who hunt in daylight? For example, bats are known to be nocturnal but are further shielded from the potential damage of radiation by virtue of living in thick-walled caves during their normal sleeping period.


  1. Steinhardt, M., Z Gerontol, 19(3):148-51 (May-June 1986).
  2. Schroeder, Dirk, Der Chlor-Report, Biel (1997).
  3. Geesing, Dr. Med. Hermann, Pep up fuer Koerper und Seele, p. 66-68 (1992).
  4. Austad, Steven N., Why we age: What Science Is Discovering About the Body's Journey Through Life?, pp. 84 and 133 [now in paperback] (John Wiley and Sons, Inc., New York; 1997).
  5. Perez-Campo R., et al, Journal of Comparative Physiology [B], 168(3):149-58 (April 1998).
  6. Herrero, A., et al, Mech Ageing Dev, 103(2):133-46 (June 15, 1998).
  7. Beckman, K.B., et al, Physiol Rev,78(2):547-81 (April 1998).
  8. Halliwell, Barry, American Journal of Medicine (September 30, 1991).
  9. Halliwell, Barry, Medical Biology, 62:72 (1984).
  10. Weindruch, Richard and Walford, Roy, The Retardation of Aging and Disease by Dietary Restriction (1988).
  11. Bischof, Marco, Biophotonen: Das Licht in unseren Zellen, (1995). [Biophotonics: The Light in our Cells]
  12. Allison, H., Physics and Longevity, Speculations(1980).
  13. Steinhardt, M., Altern. Ursachen und Biologie, pp. 16-17 (1990).
  14. Becker, Robert O., Cross Currents (1990).
  15. Markus, Dr. Michele, Heilen mit Sauerstoff (1998).
  16. Douglass, W. Campbell, Hydrogen Peroxide -- Medical Miracle (1996).
  17. Fossel, Michael, Reversing Human Aging(William Morrow and Company, Inc., New York; 1996)[German Edition].
  18. Cardus, J., Burgos, F., Diaz, O., Roca, J., Barbera, J.A., Marrades, R.M., Rodriguez-Roisin, R. and Wagner, P.D., "Increase in Pulmonary Ventilation-Perfusion with Age in Healthy Individuals", American Journal of Respiratory Critical Care Medicine (August 1997) 156 (Pt 1 of 2), pp. 648-53.
    Comment: Arterial oxygen tension (PaO2) is shown to decrease with age,

  19. Korkushko, O. V., Ivanov, L. A., Kobreniuk, T. M., "Factors in the Development of Arterial Hypoxemia in Middle-Aged and Elderly People", Fiziol Zh (March-April 1991) 37 (2), pp. 37-44.
    Comment: In elderly people, arterial blood PO2 was found to decrease (hypoxemia) secondary to defects in pulmonary capillary gas exchange.

  20. Blom, H .J., Mulder, M. F., and Verwiej, W. M., "The Effect of Age and Activity on Arterial Oxygen Pressure and Arterial Oxygen Saturation in Hospitalized Patients," Ned Tijdschr Geneeskd (May 27, 1989) 133 (21), pp. 1080-83
    ' The results show a clinically important and highly significant decline of PaO2 with age. However, it is not a linear function. In the elderly, low levels of PaO2 are encountered regularly.'

  21. King L G, Anderson J G, Rhodes, W. H., and Hendricks, J.C., "Arterial Blood Gas Tensions in Healthy Aged Dogs," American Journal of Veterinary Research (October 1992) 53 (10), pp.1744-48.
    Comment: Unlike findings in aged human beings, PaO2 was not decreased in this group of aged dogs. However, as dogs live on the average up to15 and even up to 20 years, the described group ">8 years" labeled as "aged dogs" is questionable.

  22. Another article, without abstract appeared in Neufeld, O., et al., Journal of the American Geriatrics Society (January 1973) 21 (1), pp. 4-9.
    Arterial oxygen tension in relation to age in hospital patients.
    Oxygen status in the elderly and for disease fighting:
  23. von Ardenne, M. ZFA, (July-August 1984) 39 (4), pp. 187-210.
    Age dependence of oxygen transport...
  24. Korkuschko, O. W., Z Gerontol January-February 1984, 17 (1), pp. 39-44
    Vascular changes ... tissue oxygen supply.
  25. von Zglinicki, T., Saretzki, G. Docke, W. and Lotze, C., "Mild Hyperoxia Shortens Telomeres and Inhibits Proliferation of Fibroblasts: A Model for Senescence?" Exp Cell Research (September 1995) 220 (1), pp.186-93. [Editor's Note: Hyperoxia is defined in another source as pO2 >145 mmHg]. Mild oxidative stress as exerted by a partial pressure 40 percent oxygen as exerted on a human tissue culture of WI-38 fibroblasts shows that proliferation is irreversibly blocked after one to three population doublings. Telomere lengths cut off at about 4 kbases. Single strand breaks are seen to accumulate.
  26. Rubin, H., Mechanisms of Aging and Development (October 1997).
    "[We see a] gradual reduction of cell function and growth capacity with age based on a cumulative discoordination of inteacting pathways within and between cells and tissues."
  27. Walter Pierpaoli, et al., "Theoretical Considerations on the Nature of the Pineal Aging Clock," Gerontology (1997) 43.
  28. Yong-Xing, M., Zan-Sun, W., Yue, Z., Shu-Ying, C., Zheng-Yan, Y., Long, Q., Jian-Ying, Y., Shu-Qi, C., Jian-Gang, Z., and Lin, H., "Behavior Pattern, Arterial Partial Pressure of Oxygen, Superoxide Dismutase, Micro- Blood Flow State and Longevity or Aging," Mechanisms of Ageing and Development (January 30, 1998) 100 (2), pp. 187-96.

  29. Dieter Platt, Biologie des Alterns [Biology of Aging] p. 88 (1976) based on the work of Loew, P. G. and Thews, G., "The Dependency of the Arterial Oxygen Pressure on Age in the Working Population," Klin Wschr (November 1, 1962) 40, pp. 1093-98, Ulmer, W.T.and Richel, G., "Studies of the Correlations between Age and Alveolar and Arterial Oxygen and Carbon Dioxide Pressures" Klin Wschr (January 1, 1963) 41, pp. 1-6, and Worth and Muyers (1967) in German.
  30. Michele Markus and Alexander Hoffmann, Heilen mit Sauerstoff [Healing with Oxygen] p. 14 (1998).
  31. Roland Prinzinger, Das Geheimnis des Alterns [The Secret of Aging], p. 110 (1996). [Prof. Prinzinger is a physiologist in Frankfurt, Germany].