Why don't we just stop the aging process?
Only ten conditions cause 75% of all mortalities. The top three of cardiovascular disease, diabetes, and cancer accounts for 50% of all mortalities. Are these chronic diseases age-related? Can we address them by targeting aging? A team of scientists at the University of Antwerp is fascinated by uncovering longevity signatures at the tiny molecular level and is developing an intelligent nano machine that lays the foundations for new therapies against aging and chronic diseases. They want to prevent illness occurring by avoiding the damage that lets disease in.
Prof. Stuart Maudsley, currently the Vice-Chair of the Department of Biomedical Research at the University of Antwerp and former head of the NIH National Institute on Aging Receptor Pharmacology Unit, believes in the future of nanotech therapeutics to regulate aging-induced damage in cells. He has dedicated his academic career to the field of G protein-coupled receptor (GPCR) systems and how they can be used to control the molecular signaling architecture of complex aging-related diseases. He believes it is possible to reduce the incidence rate of major mortality causing disorders, cancer, cardiovascular disease, and diabetes by developing a new class of therapeutics that intercept the disease in its early stages in a nearly imperceptible manner.
New drug system
"85% of all cancers are caused by spontaneous DNA mutations. Only a small percentage are actually inherited. The majority of them are caused by random damage. We don't want the damage to occur, we try and identify the start points of damage and stop those", says Prof. Maudsley. 'We are developing a drug system to enhance the natural level of DNA protection sensitivity."
Maudsley's team is developing the ability to subtly control these ubiquitous GPCR nanomachines that control nearly every aspect of biology or delive. "Our team has worked on therapeutics aimed to prevent oxidative damage to cells. That's what I think is the main mechanism. The big problem, that has life-long disease repercussions however, is nucleic acid (RNA or DNA) oxidation. Our body is only prepared to protect itself ideally when needed. . If I flood your system with vitamin C or other dietary anti-oxidants, what happens is your body becomes less resistant to oxidative damage as your system stops making antioxidants locally at the correct time and you lose your natural rhythmic response to local damage. That's what we are trying to avoid." The team developed a system by which you have a delivery molecule that is sensitive to oxidative damage. It creates an enhanced protective sensitivity to oxidative stress, only at the sides where there is damage. This ‘tuning’ of the stress response – without fully activating it – avoids the blunting of this important protective process.
At the tiny molecular level
The technology is a therapeutically-controlled sensor of reactive oxygen species. It already holds its delivery device. It's delivering a natural protein that controls the DNA damage response. "The amazing thing is, we had this theory now for several years, and I call it the parachute theory, this receptor is holding this coordinator. When it detects stress, they separate. The receptor goes off and becomes sensitive to the protective factors of the cell. Also, its payload is delivered to the nucleus to enhance DNA damage response, and these things form a beautiful relationship all the time across many organs in the body."
Diseases are interconnected
Maudsley has always been interested in the system. "Everything in nature is a mathematical system." He is trying to identify relevant points of the molecular signature of disease. "Diseases to me are just different combinations of numbers. Every disease is more or less the same; it's just tiny numerical combinations that distinguish disparate diseases such as Non-Alcoholic Fatty Liver Disease from Schizophrenia. They all have a central standpoint, protein expression signatures. We believe it's possible to rationally hit multiple diseases with a small number of therapeutic agents.
We barely scratch the surface
"We are not looking for therapies. We are looking for disease trajectory modifiers. If we know we are hitting the keystone in the system, we don't need to hit it that hard. This is the problem with classically-designed drugs, a single-target ‘monotherapy’ agent is a like a hammer in a complex and delicate system, it may have some beneficial effects but the collateral effects are often limiting on its usefulness. We need to look beyond this paradigm into the multidimensional nature of therapeutics. Half of the current Pharmacopeia targets are GPCRs; they have been tremendously successful in the treatment of a wide array of diseases. Half of the medications come from a one-dimensional analysis of 46 GPCRs. In fact there are at least 862 of these similar target receptors. "We don't exploit them enough. Moreover, every receptor that we know of has a functionality in at least 10 to 20 different dimensions. If we understand three dimensions, of 300 different receptors, we will generate almost a thousand different receptor targets."
The biology of life is always more complicated than you think. It's never one-dimensional. We barely scratch the surface." According to Maudsley, their drug system is the first of its type to be this third dimension of signaling. "In the present time, drug design is in the multidimensional world, and there are one or two drugs currently designed for the two-dimensional world; there is nothing in the multidimensional world. The big trick is to convince people that you are engineering a therapeutic effect that they may not overtly notice, our lab is convinced that preventing the onset of disease will have a huge impact on the generation of age-related diseases at a global leve. We have to give it some thought because patients are dying – our desire to revolutionize healthcare drives our research."
We asked Prof. Maudsley how his trajectory modifier would work out for the patient. "You would go into a clinic and have a blood sample taken. We would then take the white cells out of your blood and runs them against a panel of 20-40 proteins. It shows the specific expression pattern that is predictive of a type of disease that you are starting to develop. When you are 25 or 35, you get this done in your clinic, and the doctor informs you from your multidimensional readout thatyou are showing a 75% likelihood of cardiovascular disease when you are 50. Take this medicine and come back next week. The medicine is not designed to have a huge effect since it doesn't need to have a huge effect, it has a ripple effect on your body’s protective signaling systems. If you come back the next week and you do the same test again, the doctor says oh look, your disease likelihood has gone down to 30%. That's what we want to do." Our lab wants to create, intelligent and subtle treatments that intercept the disease and prevent it from developing into a full-blown debilitating illness.