ABRAXAS PROJECT
HEALTHY LONGEVITY VIA PREVENTION OF AGE-RELATED DISEASES:
VISION AND RESEARCH STRATEGY
by Miroslav Radman
Professor of cell biology at the University R. Descartes Medical School in Paris,
Member, French Academy of Sciences
Director & Founder: Mediterranean Institute for Life Sciences – Split, Croatia
“We will transcend all the limitations of our biology. That is what it means to be human – to extend who we are” Raymond Kurzweil
If we could prevent molecular damage relevant to cellular aging and death, it is expected that the repair and maintenance systems would work at their best, keeping all other cellular functions at high performance for possibly unlimited time. It sounds like a dream of the eternal youth, which is, however, the reality of germ line and stem cells. But, it is a dream for individual human life: to be effectively 40 or 50 years old at the age 100 or 200!
However, encouraging news appeared in a recent paper by A. Krisko and M. Radman1 showing the existence in robust bacteria (D. radiodurans) of a highly effective system (consisting of small molecules) protecting cellular proteins from damage that causes functional degeneracy and cell death. Another paper follows, showing the same, or similar, phenomenon in robust small animals (Bdelloid rotifers).
From these initial studies of robust species and our unpublished work showing large differences in the susceptibility to oxidative damage of different natural versions of the same human protein, we derive two conceptually new projects: “The biology of robustness” and “The biology of human destiny” under the common name the Abraxas (mythical elixir of youth and wisdom) Project. Both could revolutionize public health and possibly human civilization (below).
The current human life expectancy at birth is twice as long as 160 years ago and we keep living 6 hours longer every day2, 3. This is not the result of curing diseases (medicine) but of avoiding diseases (preventing diseases by hygiene, clean drinking water, quality food, and vaccination). Even if hundreds of thousands of human lives are saved worldwide by medicine, hundreds of millions do not get sick compared to the bad old times (by tuberculosis for example). Can we accelerate prevention of age-related diseases and prolong healthy life? Nothing in biology seems to forbid such ambition, and here I propose a biological approach for solving a biological problem related to public health and productive healthy longevity.
We have accepted artificial interventions into human biology by mechanical, electronic and chemical “prostheses” (medicine, in the largest sense, e.g., hearing aid, pacemakers, antibiotics, etc.). Thus, over many centuries, we fight against natural death, but wouldn’t biological intervention be a more natural approach to human biological problems? The goal would be to maintain human population in their youthful health for much longer, thereby also increasing the ratio of cultural productivity over biological reproductivity. That would ease or solve many of the burning problems of humanity, like the possibility of slowing down population growth.
Scientists have tacitly considered damage to key cellular constituents as a fatality and therefore have concentrated research on systems repairing the incurred damages, whereas medicine aimed at compensating age-related physiological deficits. But recent studies of extremely robust organisms show that the prevention of damage is the most effective strategy chosen in nature1, 4-6. Apparently, a cocktail of small molecular weight compounds present in robust species prevents oxidative damage1, 6 to cellular proteins of any species. Most importantly, protein (rather than DNA) damage is shown to be the direct cause of cellular functional defects and death1, 4,5.
Thus, the “Biology of Robustness” project proposes to identify the anti-oxidant molecular shield from robust bacteria and animals and test their protective effect on humans. New methods for quantification of protein oxidation at single cell level need to be developed in order to estimate the real biological age of each individual. Since the oxidation damage rises exponentially with age, prevention of the oxidative damage in human cells (using the anti-oxidant molecules from the robust species) is expected to slow down, stop, or even reverse (“rejuvenation”), the aging processes in humans. “Rejuvenation” is expected on account of constant turnover (synthesis of new and breakdown of old) of proteins in all cells – proteins that should be well protected from corrosion carry out both processes.
The “Biology of Human Destiny” project requires a precise quantification of oxidation of each protein in order to compare quantitatively large numbers of individuals. The key idea is that the inborn weaknesses, encrypted in the genome of each person, are masked (“silent”) at young age because the global level of protein oxidation is low and the functional defect only partial. But, at advanced age the level of oxidation raises exponentially7 and each protein variant has different susceptibility to oxidation, which progressively destroys its function – at its characteristic rate. Therefore, we are all, as life progresses, different in our destinies facing disease and death. But, not knowing the fundamental causes, we are unable to act either preventively or therapeutically.
The analysis of oxidation of each protein provides a solid theoretical framework to study molecular polymorphism in human population relative to public health. This is the first described rational approach to the individualized preventive medicine. What to do facing the fatality of our personal genes? Once born, it is too late to change genes! Remains a targeted prevention by changing the life style and/or the use of the products of “The biology of robustness” project, i.e., the general protection of all proteins – including the most sensitive ones – from the oxidative damage. Essentially, it is all about gaining the most precious commodity – the time of healthy life!
In addition, this project could provide information about special individual cases with important implications for the entire humanity. The question arises why some healthy living athletes fall victims to disease and death relatively early in their life, whereas Winston Churchill, with his unhealthy life style, has lived long lucid life? Why Jeanne Calmant lived 122 years and did not get lung cancer after having been an active smoker for over one hundred years, whereas for many unfortunate smokers it takes only about 20 years to develop lung cancer. Thus, this project is indeed about the biology of human destiny – the biochemistry of “good luck or bad luck” - encrypted in the genome of each healthy newborn child. It should allow for predictive diagnostic at young age of disease appearing at advanced age and for preventive treatments slowing down the chemistry of morbidity and mortality.
These two projects are unusual by their conceptual simplicity and the extent of potential impacts. Indeed, cultural evolution, which defines the human species, gave us the selective advantage over all other species because from its beginnings it became the instrument for transcending human biology. Here, I presented a specific approach to transcending human biology in a most natural way – by applying the recent knowledge from biology (nature).
“We humans are the only species endowed with the capacity to rebel against the tyranny of our selfish genes” Richard Dawkins
REFERENCES:
(1) Zahradka, K., D. Slade, A. Bailone, S. Sommer, D. Averbeck, M. Petranovic, A. B. Lindner, and M. Radman (2006). Reassembly of shattered chromosomes in Deinococcus radiodurans. Nature 443:569-73.
(2) Slade, D., A. B. Lindner, G. Paul, and M. Radman (2009). Recombination and replication in DNA repair of heavily irradiated Deinococcus radiodurans. Cell 136:1044-55.
(3) Krisko, A., and M. Radman (2010) Protein damage and death by radiation in Escherichia coli and Deinococcus radiodurans. Proc. Natl. Acad. Sci. U.S.A. 107:14373-7.
(4) J Repar, S Cvjetan, D Slade, M Radman, D Zahradka & K Zahradka (2010) « RecA protein assures fidelity of DNA repair and genome stability in Deinococcus radiodurans », DNA Repair, in press
(5) A. Krisko, Z. Smole; G. Debret, N . Nikolic & M. Radman (2010) Unstructured Hydrophilic Sequences in Prokaryotic Proteomes Correlate with Dehydration Tolerance and Host Association ,
J. Mol. Biol. In press
(6) O. Awile, A. Krisko, I. F. Sbalzarini and B. Zagrovic (2010) Intrinsically Disordered Regions May Lower the Hydration Free Energy in Proteins: A Case Study of Nudix Hydrolase in the Bacterium Deinococcus radiodurans, PLoS Comput Biol. 2010 July; 6(7): e1000854.
