Miroslav Radman (March 2016)

Preamble. Human body is a complex biological machine with a lifespan limited either by chronic ware and tear called aging or by an acute damage (e.g., a physical or chemical accident). Aging affects the vast majority, but not all, of biological species. For instance, hydra and medusa Turritopsis nutricula do not show manifestations of aging and some species appear almost indestructible when exposed to very high radiation doses, toxic chemicals or years of desiccation (e.g., bacteria like Deinococcus radiodurans, small animals like rotifers and tardigrades, and plants like rose of Jerrico or resurrection plant). Naked mole rat is cancer-free rodent that lives ten times longer than other rodents. At the basic level of life, i.e., individual cells, specialized differentiated cells (somatic line) undergo aging whereas non-committed stem cells (e.g., germ line), and many cancer cells, can divide indefinitely. There is clearly a biological potential for "immortality".

Molecular repair, replacement and renewal mechanisms of key biological molecules can maintain life and function of individual cells quasi indefinitely. Cellular renewal by the replacement of dying and dead cells by the young ones (issued from division of somatic progenitor stem cells) maintains the functional longevity of tissues and organs. Molecular repair and renewal processes within cells allow for their immortality. Here, I address the theme of cell protection and rejuvenation by an assisted proteome renewal replacing the malfunctioning proteome by the functioning one, in both cell types.

Human intervention in the improvement of ailing bodies started with mechanical interventions such as artificial prostheses, from mechanical limbs to hearing and visual aids and heart pacemakers. Organ transplantation is biological mechanics: replacement of a failing organ by somebody else's still functioning organ. In the course of aging, organs start malfunctioning because their cells malfunction. Therefore, instead of difficult organ transplantations, repair of ailing organs by "cell transplantation", called cell therapy, appears as an attractive alternative approach. The strategies of cell therapy aim at tissue renewal by replacing non-functional cells with functional ones through the provision of fit progenitor stem cells that will divide, specialize and function, leading to eventual restoration of organ's function. Tissue homeostasis will be the key issue in the success of cell therapy.

Proteome renewal as a natural therapy. Clearly, organisms fail when organs fail, organs fail when their cells fail, and cells fail when their molecular units of function, proteins, fail. And - proteins fail because proteins fail (in the maintenance of their own functional homeostasis facing oxidative damage to proteins). Here we reach the point of the very basis of life - the chemistry of aging and death. A new question arises: can we conceive a "protein therapy", sort of "proteomic prosthetics" that would rejuvenate in situ, not replace, the cells whose malfunction is the cause of morbidity and mortality? I believe the answer is yes because cells themselves, when appropriately assisted, are able to carry out their own rejuvenation - something that cells can do as long as they are still alive (ref. J-M Lemaitre Genes Dev paper on rejuvenation of centenarians' fibroblasts by a passage through the iPS status).

Fortunately, for the time being, there will be no need to continue to descend to more fundamental levels than proteins, because proteins are basic units of biological function required for all vital functions. Proteins synthesize all molecules - including DNA and proteins themselves - that make up cell's functioning structures, as well as metabolites required for biosynthesis and activity of all other molecules. Most proteins are sufficiently fragile to require constant replacement, on hourly or daily basis. Whereas proteins use DNA (genes) as a stable blueprint to renew unstable proteins and RNA, the DNA stability and expression depend on the activity of proteins dedicated to DNA repair, replication and gene expression (i.e., making RNA and proteins).

Protein renewal requires "protein renewal proteins" that remove non-functional proteins by proteolysis and make new functional ones (by transcription, translation, chaperoning and post-translational modifications). To maintain the proteostasis (the regulated pool of high quality proteins), cells depend on the availability of sufficiently functional "protein renewal and modification proteins". Methods are now available to monitor both quantity and quality of such proteins. This is important since their deficiency is the most likely cause of aging, and the monitoring of protein damage should facilitate the selection of remedies against aging as well as simultaneous prevention, and eventual cure, of all age-related diseases.

A concept of aging and of common cause of all age-related diseases. This concept arose in the course of a decade of our research on extremely robust organisms. Now, the results that have inspired the concept are not important since other kind of data could have led to the same concept. What matters is whether the concept is correct because it is supposed to explain the common cause and the general mechanism for most, or all, of age-related diseases and aging itself. The concept should guide research towards the precise identification of the cause of each individual age-related disease and that of the process of aging. This should lead to the predictive diagnostic, prevention, and even cure of age-related diseases.

The concept is that aging and age-related diseases are the snowballing phenotypes of oxidative damage to proteins that accumulates exponentially with age. The inter-individual differences in face of increasing age can be accounted for by protein polymorphism underlying the polymorphism of intrinsic oxidability of individual proteins. Most proteins are oxidation-resistant in their native form, but even single amino acid substitutions (polymorphisms) and random errors can cause increased susceptibility to oxidation and predispose to disease.

 In other words, age-related phenotypic changes are caused directly by damage to function (proteins) and age-related diseases result from the progressive transition of non-phenotypic ("silent") mutations (polymorphisms) into ("loud") phenotypic mutations due to oxidative damage affecting proteins sensitized by mutation. Unlike DNA mutations that destroy protein or RNA function causing disease phenotypes at birth (syndrome), the silent mutations do not destroy but only fragilize protein function. Perturbing native structure/stability increases protein susceptibility to oxidative damage and shortens its functional longevity. Silent polymorphisms appear as conditional "chrono-sensitive" mutations whose phenotype emerges and progresses with biological age.

Treating aging and age-related diseases. Reduction in ROS by effective antioxidants should lead to a progressive replacement of oxidized proteins by new and protected ones. Because of the described feedback loops in proteome homeostasis, just as the bad news (accumulation of damaged proteins) grow exponentially during aging, the good news (clearance of damaged proteins) must also grow exponentially, but in the opposite direction - rejuvenation of proteins and cells.

Potential complications: somatically acquired DNA mutations will remain even after proteome rejuvenation and the extracellular matrix proteins (e.g., keratin, elastin, amyloid-beta), although subject to renewal, may be slow to replace... This aspect is elaborated in the Cancer Latency project.

Prevention of aging and age-related diseases. Here, the goal is to slow down the rate of accumulation of protein damage expecting a delay in all manifestations of aging. A curative effect of this "generic" anti-ROS approach can also be anticipated. Unlike in the therapeutic proteome rejuvenation, we do not anticipate complications from the rejuvenation therapy by the use of effective antioxidants in prevention of aging and the associated diseases when the sole purpose is in maintaining protein damage at just as low levels as in young persons. Again, cancer is a special case because apoptosis requires oxidative stress and there is recent evidence that the transition of initiated (pre)cancerous cells to cancer cells can be accelerated by anti-oxidants, i.e., anti-oxidants may well prevent early events in cancer but stimulate its development. However, cancer cells live with high redox potential and undergo progressively increased protein oxidation during the development of malignancy, such that lowering redox potential could handicap specifically cancer cells. This complication is dealt with in the Cancer latency project.

Prevention and cure of age-related disease via protection of fragile proteins against oxidative damage. Although D. radiodurans and ES cells live fine with very low levels of ROS and protein damage, some low level of ROS may be necessary for normal functioning of differentiated cells (see Watson, 2013, 2014). Thus, one could anticipate that the dosage of neutralization of ROS by scavenger molecules will be difficult to tune in vivo in order to obtain the desired beneficial effect. In that case, we can think of targeted protein protection without affecting the physiological levels of ROS. For instance, one can use selected or synthesized "band aid molecules" stabilizing the structure of the vulnerable protein relevant to the disease or protecting the site of oxidative damage on the incriminated protein. When such disease-relevant protein polymorphism is diagnosed, then the "band aid" can be applied preventively starting from the young age or therapeutically after the emergence of disease. This approach stipulates a previous identification of polymorphic mutations that predispose to age-related diseases due to an increased susceptibility of the relevant protein to oxidative damage.

Unlike organ transplantation and stem cell therapy that can have beneficial effects localized to an organ or tissue, the proposed "protein therapies" are systemic either by renewing organism's proteomes or by protecting a specific fragile protein wherever it is synthesized in the organism. This concept is patent-protected (M. Radman, A. Krisko, Protein damage in aging and age-related diseases, Intern Patent Publ No: WO 2014/125376 A2; PCT/IB2014/000/700)


A proposal for cooperation with pharmaceutical industry

by Miroslav Radman (17/05/2016):

Prevention and reversion of age-related diseases

We have uncovered the fundamental chemistry of aging and age-related diseases. We have also identified the root cause of a degenerative disease (Parkinson's disease), elaborated the strategy to identify the causes of other age-related diseases and defined an approach to protect or restore the function of the 'weakest link' in every person's health!

A completely new class of pharmacological molecules will be needed. For each person, the same molecule will be used to prevent and treat (the cause of) disease by correcting specific protein defect in a way conceptually similar to Vertex Pharmaceuticals' approach to cystic fibrosis (CFTR structure corrector).

We estimate to 100-200 ancestral protein polymorphisms (to be identified!) as the cause of predisposition to the ensemble of age-related diseases in human population. Therefore, that many specific molecules will be needed to both prevent and revert nearly all age-related diseases. To avoid disease, the entire human population will potentially take such (person-specific) molecules to suppress the innate functional fragility of oxidation-sensitive versions of polymorphic proteins. Proteins, not genes, will be subject to protection of biological function eroded by oxidative damage in an age-related (exponential) fashion.

This approach presents a true revolution in public health - a democratisation of health! The health-related genetic inequality could be remedied by an a priori equal cost of each of a few hundred molecules that, together, will be counteracting (preventing and healing) all age-related diseases as long as the medication is being used. By correcting the functional defect causing each age-related disease, the pool of new drugs should replace drugs used today to treat symptoms of degenerative diseases. By acting successfully upon main causes of mortality, new drugs will extend human health span and prolong productive life.