Prevention of Age-related Diseases and
Extension of Healthy Life
The gist of a project proposed by
Miroslav Radman
Medical School of the University R. Descartes - Paris 5 (exceptional class professor),
French Academy of Sciences (member), and
The Mediterranean Institute for Life Sciences, Split, Croatia (co-founder and director)
Two biological clocks determine the destiny of all living species and organisms: (1) The universal clock of genetic change in the germ line, common to all species (evolutionary destiny), and (2) The species-specific somatic clock determining the kinetics of emergence of age-related diseases and death of individual organisms (individual destiny). The cancer clock is part of the species-specific somatic clock. The chemistry of these two biological clocks is not known, and this project proposes to study both of them.
New Methods
We have recently developed methods for:
(A) Measuring global genomic mutation rates in any living cell, including the germ line cells (M. Elez, I. Matic & M. Radman, Current Biology, 2010). The chemistry of the germ-line clock is clearly DNA chemistry, but we do not know the origin and the causes of DNA changes (mutations) assuring adaptive evolution of species as well as of hereditary diseases and cancer.
(B) Measuring the somatic clock, i.e., the fundamental biochemical event(s) responsible for the progressive loss of biological fitness in the course of aging (so-called intrinsic aging). We found that the chemistry of the somatic clock is protein chemistry, i.e., the accumulation of protein damage due to the oxidation (carbonylation) of their amino acids (“corrosion”) causing loss of protein function and/or decreased precision of interactions among proteins (A. Krisko & M. Radman, PNAS 2010; A. Krisko, M. Leroy, M. Radman & M. Meselson, submitted). The quantitative test of proteome damage and cell fitness can be called “bio-gerontometry”.
The Biology of Robust Species
Some rare species (e.g., bacteria like Deinococcus radioduransand small aquatic animals Bdelloid Rotifers and Tardigrada) show stunning resilience to stresses such as extreme radiation, toxic chemicals and years of radical dehydration (desiccation) that kill most species over hundred times. By studying the molecular biology of such species, we found that their robustness is due to the evolved prevention of the oxidative damage to cellular proteome – the functional entity of life – not to prevention of DNA damage. The anti-oxidant protection against proteome damage is assured by the synthesis of small molecular weight (
We found that the protective molecules from robust species protect equally effectively proteomes from resistant and sensitive species. This trans-species protective activity is the basis of our hope that that such protective substances may protect the human proteome from debilitating damage caused by radiation, chemicals and possibly age. Hence, a reasonable perspective of eventual slowing-down of the rate of aging and all age-related diseases, or “geronto-therapy”.
The “Biology of Human Destiny” and the Individualized Preventive Medicine
Clearly, being overweight, smoking and consuming alcohol is deleterious to human health. But, why some individuals, healthy and athletic at young age, and living a healthy life style, die relatively early of some disease, whereas others doing the opposite (e.g., Winston Churchill) live long and lucid life? Jeanne Calmant smoked hundred years, lived 122 and did not dye of cancer. According to Dr. James Vaupel (MPI for Demography) Mrs. Calmant visibly aged just as fast as her centenarian congeners, but unlike others, was healthy, i.e., she had no overt constitutive weakness that would terminate her life earlier. Is it possible that everybody is predisposed to the particular life-terminating disease?
Predispositions to specific diseases that are expressed at some advanced age often run in families. I hypothesize that most of individual genomic “silent polymorphisms” - obviously silent at young age when people are still healthy - become progressively “loud” (i.e., phenotypic) at advanced age when disease is manifested. But, what is the molecular basis of such predispositions to specific diseases occurring only at advanced age and how they can be diagnosed? I believe that we are on the track of answering this question (below).
With the laboratory of Thomas Nystrom in Goteborg, we have shown that subtle changes in protein structure can drastically increase the susceptibility to oxidative damage (carbonylation) (Dukan et al. PNAS (2000) 97: 5746-5749; Fredricksson et al., Genes Dev. (2007) 21:862-74). Recently, we have observed that naturally occurring “morphs” (single amino acid substitution) of a protein related to Parkinson’s disease can exhibit increased susceptibility to carbonylation by up to 15-fold (A. Krisko & M. Radman, in prep.). The in vitro susceptibility of this purified protein to H2O2 and radiation-induced carbonylation correlates with the early onset of the disease in the patient. The tentative interpretation is that – at advanced age when global protein carbonylation increases exponentially (Oliver et al., JBC (1987) 262:5488-5491) – individual polymorphic proteins start “burning out” by oxidation at different rates in different individuals causing eventually the progressive deficit of their function and advancing disease. In other words, even when healthy at young age, we are all predisposed to some diseases that will appear at advanced age with similar exponential Gompertz kinetics and eventually cause disease and death. That predisposition is encrypted as part of the “silent polymorphism” in the coding fraction (about 1.5 %) of our genome and becomes “loud” (phenotypic) at advanced age. Can such predispositions be identified at young age?
Here is an experimental strategy: If we could detect and diagnose individual’s inborn susceptibilities to spontaneous and oxidative stress-induced protein carbonylation of individual proteins (spots in 2D gels), we may be in position of reading, in young persons, their health-related destiny at advanced age.
Suppose that we would succeed in this predictive diagnostic. What can be done about the predicted fatality? First, one can apply the common sense preventive life style, and second, hope that the most effective known biological anti-oxidant complex from the robust species would act adequately in humans thereby delaying the disease-related destiny.
Since we are obviously all predisposed to suffer from some specific disease(s) before the onset of other diseases, everybody would want to take the preventive anti-oxidant treatment. What can be expected from such treatment? Even the cellular malignant phenotype may be subject to delay, because the “phenotypic expression” of recessive mutations in tumor suppressor genes is likely due to the functional “memory” of the relevant protein (once both gene copies are inactive) that can be shortened by the oxidative inactivation of the remaining tumor suppressor protein, e.g., during inflammatory processes (tumor promotion).
Extension of Healthy Life: Young at 100 years?
Almost all proteins are “turned-over”, i.e., synthesized and then broken down. Therefore, the measured level of carbonylation in human fibroblasts results from a steady state of incurred protein carbonylation and the selective breakdown of carbonylated proteins by the dedicated 20S proteasome (which is also made of proteins that are subject to carbonylation). Therefore, if the anti-oxidant complex from robust species is taken chronically, and is effective, then the old oxidized proteins should eventually get degraded, and the protected newly synthesized proteins would be maintained at low level of oxidative damage. Therefore, the proteome is expected to “rejuvenate” resulting in the improvement of all cellular functions (including the telomerase) and organism’s biological fitness. Consequently, one can expect that not only the increase in the rate of aging ceases, but that an effective rejuvenation takes place.
This is of course a science fiction scenario, but human life span keeps increasing 6 hours every day without implementation of any particular plan or strategy (J. Oeppen & J.W. Vaupel, Science, 296: 1029-31, 2002). Thus even a small chance of success is worth trying.
The virtue of this project is the simplicity of concepts and the feasibility of experiments. Everything that looks so complicated in aging could become but a detail of this simplicity. For instance, we find that DNA repair is limited by the level of oxidative damage to DNA repair proteins with direct consequence to genomic integrity. Chromosomal telomeres may be shortening with age because the enzyme telomerase becomes inactivated by oxidative damage, etc. The proteome protection is probably reprogrammable because we find 10 times more protein carbonylation in fibroblasts than in embryonic stem cells of the same mouse strain, and the derivation of IPS cells from differentiated ones leads to a decrease in protein carbonylation levels in the course of time/growth (unpublished).
Amusing questions
Interesting questions arise relative to this project. While almost everybody looks forward to a long and healthy life, is there any positive societal interest in prolonging healthy life of the entire population? Given the monumental expenditures for health care causing huge budgetary deficits, prevention of diseases would liberate large governmental and insurance funds for other priorities. More importantly, prevention of disease eliminates the suffering due to disease even when the therapy is successful.
Provided its success, when should one start the “rejuvenation treatment”, before or after the menopause? Extension of healthy life would cause an increase in the ratio of productive to reproductive persons, and the population growth would presumably slow down which may be beneficial to humanity’s destiny. Human biological evolution, already too slow for adaptation to fast changing life conditions, would presumably somewhat slow down, but young centenarians could generate an explosion in cultural evolution. Finaly, imagine what would happen to the existing (insufficient) human solidarity when the most important element of equality – the equality in face of death – would vanish if the “elixir” is not available to everybody free of charge?
