MECHANISM OF AGING
Can we grow young again? Trials that can change the lives of billions
I have formed a view regarding the mechanism of aging, not the switches that turn it on, only the mechanism. In our body DNA damage is very frequent, occurring on average about 60,000 times a day per cell of the human body but this is not the cause of aging. The rate of damage is the same for the young and the old - what changes as we age is the rate and efficiency of repair. At any given moment, there's competition in your body between cellular damage and repair. As the damage becomes greater than your body's ability to repair and regenerate, deterioration sets in. "If we could repair damage as fast as it occurs, we could live forever," says Dr. Rosedale. Another competition is between growth and repair. When one is dominant the other is muted. Too much repair beyond what is needed can become harmful to healthy cells and so is too little. So Nature has created activators and inhibitors and sensors. In our prime the opposing forces move the steering wheel left and right efficiently so that the repair car remains in the middle of its lane but as we age one begins to dominate the other (for example inhibitors overpower the activators) causing the snowballing feedback loops and dysfunctions which slacken the pace of repair, on a sliding basis, leaving unrepaired damage. Their dysfunction increases systemic damage including to the organs. What would happen if the steering wheel is pulled only on one side more and more? The repair car will soon veer off road and sooner or later is destined for a fatal accident. Yin and Yang a 3rd century BC gift of Taoism figured out Nature's system of opposing forces maintaining an equilibrium - agonists and antagonists, push and pull - how seemingly opposite or contrary forces may actually be complementary, interconnected and interdependent in the natural world and how they may give rise to each other as they interrelate to one another - as described in Wiki. Multiple reactions with intricate networks of activators and inhibitors are involved in biological homeostasis. Homeostasis is maintained by a series of control mechanisms functioning at the organ, tissue or cellular level. These control mechanisms include substrate supply, activation or inhibition of individual enzymes and receptors, synthesis and degradation of enzymes and compartmentalization. Despite its complexity biological systems are after all finite. And all finite problems can be solved. Restoring the equilibrium found in our prime between damage and repair can cure aging. When young blood is transfused in old it temporarily rejuvenates the equilibrium of the repair systems by the circulating young factors. But the transcriptional program resumes destabilizing the balance between the opposite forces to ensure repair gets weaker again and progressively. Clearing senescent cells or lengthening telomeres or upregulation of NAD+ are resurrecting some parts of the dysfunction. Only restoration of full equilibrium in the repair machinery vis-a-vis damage can cure aging as a whole.
 An example: A recent exciting development in the field of anti aging has been the discovery of a molecule called FOXO4-DRI by
Cell biologist Peter de Keizer of Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues. When the cells face damage, repair machinery remedies the damage and revives the cell. Sometimes the damage is beyond repair. At such time cell adopts a process called Apoptosis and dies or is recycled by a process called Autophagy. If for any reason a severely damaged cell misses both, the cell becomes a zombie - senescent cell. Senescent cells secrete poisons which affect surrounding healthy cells. As we age and the forces inhibiting our repair systems begin to dominate over repair activators it begins to reduce our repair efficiency. This creates more and more senescent cells. They tend to clog our tissues and organs and cause progressive damage to them. But Nature has made a cure for them to keep a check on how many senescent cells remain. P53 is a tumour suppressor protein that binds to senescent cells and helps them achieve apoptosis. But as we read above Nature keeps a inhibitor to ensure there is not too much of P53. This is another protein called FOXO4. It binds to P53 and blocks it's ability to help senescent cells achieve apoptosis. In our prime the opposing forces of P53 and FOXO4 balance at levels to create optimum clearance of senescent cells. As some amount senescent cells are needed for wound healing and they are also a valuable raw material in the genesis of new cells. But as we age this balance too is disturbed wherein too many of the P53 inhibitor FOXO4 are produced which in turn multiplies the numbers of senescent cells which continue to multiply the damage in the system, tissues and organs. This is a classic example of the Yin and Yang losing its optimal balance. FOXO4-DRI is a synthetic molecule that has higher affinity for P53 - it wins the competition with FOXO4 in binding with P53. This allows P53 to complete it's task of enabling senescent cells achieve apoptosis. It has shown remarkable reversal in certain aging markers on mice. Old mice regained thick coat of fur seen in young mice and were able to do tasks that they did when they were young. An intervention that restores the optimum balance between inhibitors and activators can potentially undo damage and reverse aging helping us regain our youth.
Another Example: PARP1 is an enzyme that is essential in initiating various forms of DNA repair. DBC1 binds to PARP1 and prevents it from executing DNA repair. So it becomes a inhibitor. Each inhibitor should have a corresponding activator - in this case NAD+ plays that role. NAD+ prevents DBC1 from binding with PARP1 and thus ensures DNA repair. As we age the levels of NAD+ decreases by which increases the binding of DBC1 with PARP1 the result: DNA breaks go unrepaired and as these breaks accumulate over time, precipitate cell damage, cell mutations, cell death, and loss of organ function. David Sinclair’s lab at Harvard Medical School observed that when NAD+ levels were restored the markers showed improved DNA repair. Thus here too we see that restoring the optimum balance of inhibitors and activators brings back youthful levels of repair.
As we age we see our body shape, fitness, skin, hair and our face change gradually but visibly. When we compare our photos of age 25 and age 75 we look so dramatically different - we find our 25 year old self better looking and more attractive. The difference between the two is the damage that slips by the repair machinery. One can see how mercilessly it chisels away the radiant beauty of youth. Since we have seen others also suffer this damage without question we too accept this trauma and tragedy as normal. A few tweaks may be all that may be required to not only avoid these debilitating changes but potentially reverse them. We assume that all of us is as old as our age but except for neurons of the cerebral cortex we are not more than 15 years old. As everything inside us renews and recycles itself. Sperms life is only 3 days, taste buds 10 days, lungs 3 weeks, skin which carries our outward appearance just 2-4 weeks, liver 150 days, bones 10 years, etc. We always look at reversal of age very sceptically but now that you have this perspective it brings it back in the realms of possibilities. So my question is: if damage caused by aging is reversible (as confirmed by recent studies Hayashi Tsukuba University) and if we are able to bring back the optimum balance between repair system inhibitors and activators why would a 75 year old not begin to look and feel like his 25 year old self again??? My venture is hoping for that to happen. In collaboration with a reputed University we are launching pre-clinical trials on old lab mice where my proprietary protocol of interventions (a fruit of many years of research and analysis) may bring back the optimum performance of their repair systems. Hopefully this in turn may make the old mice young again. There have been many anti-aging experiments around the world which have been able to extend the life of lab mice by 5% to 50%. Our quest is to maintain repair system biochemical homeostasis and keep the reversal to youth sustainable. I will be able to update you with the results within a few months. The tests are for safety, dosage, bioavailability and efficacy. If we are successful we plan to conduct human clinical trials next in collaboration with a reputed hospital. Wish us luck and success
