UPDATE: MECHANISM OF AGING THEORY
One more evidence
DKFZ The German Cancer Research Center is Germany's largest biomedical research institute with a thousand scientists. On 20th June 2018 they reported a discovery in the field of aging. I will quote some of what they report: 'Oxidative stress causes cells and entire organisms to age. If reactive oxygen species accumulate, this causes damage to the DNA as well as changes in the protein molecules and lipids in the cell. The cell ultimately loses its functionality and dies. Over time, the tissue suffers and the body ages. "The theory of oxidative stress or the accumulation of reactive oxygen species as the cause of aging has existed since the 1950s," says Peter Krammer of the German Cancer Research Center (DKFZ). "So far, however, the details of this process were unclear."
One way in which the body disposes of harmful reactive oxygen species is their conversion by the enzyme thioredoxin-1 (TRX-1). TRX-1 has been proven to play a role in protecting DNA from oxidative stress and slowing down aging processes. Its antagonist TXNIP inhibits thioredoxin-1 and thus ensures that the reactive oxygen molecules are retained.
In fact, reactive oxygen species (ROS) do more than just damage the body. For example, they are essential for the T-cells of the immune system to become active.' So ROS is also beneficial in the right proportion. The key is for excess ROS to be processed away before it can become harmful. But inversely, too much TRX-1 can impair critical immune related activity triggered by ROS. As I have stated in my earlier blog post called 'Mechanism of Aging' Nature modulates levels by using agonist and antagonists. It's like a hot water tap and a cold water tap and one can adjust their output to get water at just the right temperature. Where water represents repair pathway. Excess of either cold or hot can make it painful and harmful for us. Just the right temperature is called homeostatic state in our biology.
When we are young the agonists Trx1 and antagonists TXNIP maintain just the right levels of ROS. But as per theory proposed in my earlier post ' Mechanism of Aging' Nature selectively increases the levels of antagonists as we age in a progressive manner. This begins to progressively increase the levels of ROS. To continue with my comparitive example it's like cold water is drowned out by increasing levels of hot water. At one point it begins to scald. That is what happens with uncontrolled ROS damaging for example DNA to a scale at which DNA's repair enzymes can't keep up. Nature by the way also modulates DNA repair systems with agonist and antagonist molecules. DNA repair is activated by PARP1 whose antagonist is DBC1 and agonist is NAD+. So can you see a pattern emerging here? TXNIP domination over TRX-1 as we age leads to rising ROS levels. One of the damage excessive ROS causes is to DNA. But as we age and just when DNA needs it most DBC1 levels also begins to dominate over NAD+ levels. So ROS causes more DNA damage just when less and less repair enzymes are available to repair it. Mounting unrepaired DNA damage then leads to rising mutations and genomic instability.
I am excited by the DKFZ findings as it corroborates the theory proposed in mechanism of aging post on this blog of how aging program is implemented in our body. What you read above is happening in all major repair pathways and it snowballs progressively making death unavoidable. But what would happen if we selectively upregulate the dwindling agonists of repair? In the case of upregulation of NAD+ David Sinclair's lab at Harvard Medical School showed that DNA repair markers improved. Similarly the DKFZ researchers led by Krammer and Gülow wanted to know whether more TXNIP is formed in the body with increasing age, thereby undermining the protective mechanism against oxidative stress. To this end, they first compared T cells from the blood of a group of over 55-year-old volunteers with the T cells of younger blood donors, who were between 20 and 25 years old. In fact, it turned out that the cells of older subjects produce significantly more TXNIP. The DKFZ scientists have also observed similar findings in other human cell and tissue types. They also found TXNIP levels similarly much higher in older flies. Upregulation of TRX-1 would balance out the higher levels of TXNIP thereby forestalling the damaging chain reaction of rising ROS levels.
Another Evidence:
Autophagy is a very important repair and recycling pathway. With aging this too progressively goes down in efficiency leaving more and more senescent cells. It's importance can be gauged by the $307 million raised by Unity Bio based on pre-clinical data about a molecule that can clear senescent cells. One of their investors is now the world's wealthiest man Jeff Bezos founder of Amazon.
As cells die autophagy recycles the dead cells into new cells and clears debris. If this doesn't happen efficiently, aging humans are left with dead zombie cells (senescent cells) that secrete damaging cytokines harming surrounding healthy cells leading to mounting damage in tissues and organs.
Alvaro Fernandez and Salwa Sebti along with colleagues at University of Texas Southwestern Medical Center, USA published a study in Nature Journal on 30th May 2018. As per theory of mechanism of aging posted on this blog there is negative regulator of autophagy - antagonist called BCL2. It interacts with Beclin 1 a regulator of autophagy and apoptosis and blocks autophagy. As we age guess what happens. BCL2 increases it's interaction with Beclin 1. When the scientists disrupted this interaction between them it increased autophagy. Just bringing up one major repair and recycling pathway back to youthful levels not only increased healthspan but also lifespan.
Another Evidence:
Autophagy is a very important repair and recycling pathway. With aging this too progressively goes down in efficiency leaving more and more senescent cells. It's importance can be gauged by the $307 million raised by Unity Bio based on pre-clinical data about a molecule that can clear senescent cells. One of their investors is now the world's wealthiest man Jeff Bezos founder of Amazon.
As cells die autophagy recycles the dead cells into new cells and clears debris. If this doesn't happen efficiently, aging humans are left with dead zombie cells (senescent cells) that secrete damaging cytokines harming surrounding healthy cells leading to mounting damage in tissues and organs.
Alvaro Fernandez and Salwa Sebti along with colleagues at University of Texas Southwestern Medical Center, USA published a study in Nature Journal on 30th May 2018. As per theory of mechanism of aging posted on this blog there is negative regulator of autophagy - antagonist called BCL2. It interacts with Beclin 1 a regulator of autophagy and apoptosis and blocks autophagy. As we age guess what happens. BCL2 increases it's interaction with Beclin 1. When the scientists disrupted this interaction between them it increased autophagy. Just bringing up one major repair and recycling pathway back to youthful levels not only increased healthspan but also lifespan.
Now as promised I am sharing very good news for all who wished us luck for our pre-clinical trials mentioned in the post Mechanism of Aging: We have the results of a 2 month study where we selectively administered natural molecules and compounds that upregulate major known repair pathways. First of all safety tests cleared with flying colors histopathologist could not distinguish between young and treated old tissues. The main trial results were also spectacular: chronic inflammation of treated old rats reversed all the way back to levels of young control rats! Muscle strength - grip strength of old treated rats went up almost reaching young control rats! And cognitive skills - memory test scores of old treated rats were close to young control rats! The old treated rats lost weight despite having same amount of feed as old untreated rats! There was a wide difference between the levels of old treated rats and old untreated rats. If these are some of the key markers of aging did we reverse the age of old treated rats back to youth? It was equivalent of a 70 year old developing the metabolism, strength and memory of a 20 year old. Does it prove the theory of how Nature implements it's aging program? The anti aging benefit derived by rapamycin and metformin are limited and triggered only in a narrow range as it is a hormetic intervention. Anti aging benefits derived by resettng gene expression which has been methylated by aging changes to the epigenome theoretically may not be restricted by a narrow bandwidth. We have to find out over hundreds of studies whether this can be the fountain of youth we have been searching from thousands of years. Now on to human clinical trials. Please wish us luck.
