CANCER & AGING: II. Aging Starts at 15 and not 50!
AGING: Two clues have emerged that shocked me with the realisation that aging starts just after puberty! These two studies also add two more evidences that aging is not due to accumulation of errors or wear and tear over time but due to direct missiles fired by pre-installed instructions just after the formation of reproductive organs. One of them collapses the support system to the protein formation machinery and the other attacks the heart cells. These are just two that have been discovered but there must many more such secret attacks that begin the process of deterioration of our biology.
After water proteins have the second highest weight in our body. There are probably more than 30,000 types of proteins that are manufactured from our DNA and the proteasome machinery that do multiple tasks including transcribing and translating instructions from our genes to our cells, act as hormones, enzymes and part of immune system. Proteins are born in long strips which are then folded into a particular shape. This shape decides it’s function. If there is misfolding it can become damaging. So nature has added multiple chaperones to help it fold correctly and if any still slip by then to avoid damage they are degraded by ubiquitin protease system and autophagy. Soon after puberty Germline Stem Cells GSCs send a signal to this important support machinery to collapse it’s efficiency by as much as 70%. This seems to be the first identified assault of aging. From then onwards more and more proteins come out misfolded and worst are not degraded so clump together to create sticky aggregates which disturb many cellular functions leading to damage and disease.
The ribosome makes mistakes in as many as 1 in every 7 proteins! Even under normal conditions, up to 30% of all cell proteins fail to fold properly, and are immediately degraded. Protein folding is a very sensitive process that is influenced by several external factors including electric and magnetic fields, temperature, pH, chemicals, space limitation and molecular crowding. These factors influence the ability of proteins to fold into their correct functional forms.
Scientists have pinpointed the start of aging and discovered it is not a slow series of random events. Two Northwestern University scientists have identified a molecular switch in the transparent roundworm C. elegans, that abruptly begins cell aging just as the animal reaches reproductive maturity.
A genetic switch starts the aging process by turning off the cell's ability to respond to stress. Responding to stress would otherwise protect a cell by keeping essential proteins folded as well as functioning. The switch is thrown by germline [sperm and egg] stem cells in early adulthood, after reproduction begins.
While the studies were conducted in worms, the genetic switch and other components identified by scientists as part of aging, are conserved in all animals — including humans. And as C. elegans has a biochemical environment similar to our own, it is a popular animal model for human disease and for human aging.
"Wouldn't it be better for society if people could be healthy and productive for a longer period of their lifetime? I am very interested in keeping the quality control systems optimal as long as we can, and now we have a target. Our findings suggest there should be a way to turn this genetic switch back on and protect our aging cells by increasing their ability to resist stress." said Richard Morimoto PhD, the Bill and Gayle Cook Professor of Molecular Biosciences, director of the Rice Institute for Biomedical Research, Weinberg College of Arts and Sciences, Northwestern University.
Once the germline has completed its job and 1) produced eggs and sperm needed to create the next generation, it 2) sends a signal to cell tissues to turn off protective mechanisms and begin the decline of the adult.
In one experiment, researchers blocked the germline from sending the signal to turn off cellular quality control, and found the somatic tissues remained robust and stress resistant.
Morimoto: "This was fascinating to see. We had, in a sense, a super stress-resistant animal that is robust against all kinds of cell stress and protein damage. This genetic switch gives us a target for future research."
Study’s finding that the loss of stress protection responsiveness in C. elegans is a result of failure to clear a single repressive chromatin modification, which interferes with a heat shock factor (HSF-1) binding event, which in turn suppresses transcription initiation in response to stress.
The molecular mechanism is particularly intriguing, as it involves a signal from germline stem cells that decreases expression of a specific demethylase enzyme, resulting in elevated levels of a repressive class of histones targeted to the genes for cell stress responses. The consequence: a rapid, coordinated inhibition of stress survival mechanisms.”
Here again we see what I pointed out in my last post Mechanism of Aging - Nature's calibration happens through tuning of activators and inhibitors.
They demonstrate that HSF1-promoter accessibility sharply declines on the second day of adulthood. This is strongly associated with sharply increased levels of H3K27me3 marks at the promoters of heat shock genes, a hallmark of transcriptional repression [that results in dysfunctional protein production]. This demonstrates, for the first time, that the repression of the heat shock response is regulated, and that epigenetic changes modulate the animals’ ability to respond to stress after reproduction onset.” “discovered that enhancing this demethylase (jmjd3.1), which is conserved to humans, prevents this decline in stress resilience, and results in animals both robust and long-lived.”
In a separate study Lead author Dr Sean Byars from the University of Melbourne says the team wanted to understand more about how CAD (coronary artery disease) has been inherited in our evolutionary past, in order to better understand why it is so common presently. "CAD is often thought of as modern disease, but actually atherosclerosis, or thickening of the artery walls, has been detected in Egyptian mummies, so we suspect it has been in our genes for thousands of years."
CAD currently affects 110 million people and causes 8.9 million deaths annually, from 2015 figures.
"According to the theory of natural selection, as proposed by Charles Darwin, genes for traits that improve individual survival or reproduction will increase or be maintained in populations, whereas those that reduce these will be selected against and gradually removed or reduced over time. "So it is unclear why CAD is so common in modern humans and this is important to understand given the global health burden it represents," explains Dr Byars.
Associate Professor Michael Inouye, who also led the study, said the findings showed that many genes associated with CAD have actually been positively selected for through evolution.
"After further research, we found CAD genes are also important for reproduction and that these genes are involved in important functions in male and female fertility being expressed in the testes, ovaries and endometrium, for example," said Assoc Prof Inouye, based at the Baker Heart and Diabetes Institute.
So in this case too same genes which were important and beneficial during reproduction biology later flip a switch and become very harmful by causing CAD – the leading killer in humans.
These studies show that for Nature once the primary function of reproduction is done the body becomes only a competition for resources for the new born and is to be bumped off. What is shocking is that aging begins its damage just after we reach reproductive maturity – puberty. By the time we begin to see the effects of this build up of damage around 50 years of age it is already too late and a lot of the damage is done. Although this shows how complex is aging disheartening the anti aging crusaders, a clue also emerges: the changes that initiate the damage are actuated by new epigenetic marks. A permanent cure for aging may lurk in the corridor of the epigenome and the transcription factors.
AGING: Two clues have emerged that shocked me with the realisation that aging starts just after puberty! These two studies also add two more evidences that aging is not due to accumulation of errors or wear and tear over time but due to direct missiles fired by pre-installed instructions just after the formation of reproductive organs. One of them collapses the support system to the protein formation machinery and the other attacks the heart cells. These are just two that have been discovered but there must many more such secret attacks that begin the process of deterioration of our biology.
After water proteins have the second highest weight in our body. There are probably more than 30,000 types of proteins that are manufactured from our DNA and the proteasome machinery that do multiple tasks including transcribing and translating instructions from our genes to our cells, act as hormones, enzymes and part of immune system. Proteins are born in long strips which are then folded into a particular shape. This shape decides it’s function. If there is misfolding it can become damaging. So nature has added multiple chaperones to help it fold correctly and if any still slip by then to avoid damage they are degraded by ubiquitin protease system and autophagy. Soon after puberty Germline Stem Cells GSCs send a signal to this important support machinery to collapse it’s efficiency by as much as 70%. This seems to be the first identified assault of aging. From then onwards more and more proteins come out misfolded and worst are not degraded so clump together to create sticky aggregates which disturb many cellular functions leading to damage and disease.
Scientists have pinpointed the start of aging and discovered it is not a slow series of random events. Two Northwestern University scientists have identified a molecular switch in the transparent roundworm C. elegans, that abruptly begins cell aging just as the animal reaches reproductive maturity.
A genetic switch starts the aging process by turning off the cell's ability to respond to stress. Responding to stress would otherwise protect a cell by keeping essential proteins folded as well as functioning. The switch is thrown by germline [sperm and egg] stem cells in early adulthood, after reproduction begins.
While the studies were conducted in worms, the genetic switch and other components identified by scientists as part of aging, are conserved in all animals — including humans. And as C. elegans has a biochemical environment similar to our own, it is a popular animal model for human disease and for human aging.
"Wouldn't it be better for society if people could be healthy and productive for a longer period of their lifetime? I am very interested in keeping the quality control systems optimal as long as we can, and now we have a target. Our findings suggest there should be a way to turn this genetic switch back on and protect our aging cells by increasing their ability to resist stress." said Richard Morimoto PhD, the Bill and Gayle Cook Professor of Molecular Biosciences, director of the Rice Institute for Biomedical Research, Weinberg College of Arts and Sciences, Northwestern University.
Once the germline has completed its job and 1) produced eggs and sperm needed to create the next generation, it 2) sends a signal to cell tissues to turn off protective mechanisms and begin the decline of the adult.
In one experiment, researchers blocked the germline from sending the signal to turn off cellular quality control, and found the somatic tissues remained robust and stress resistant.
Morimoto: "This was fascinating to see. We had, in a sense, a super stress-resistant animal that is robust against all kinds of cell stress and protein damage. This genetic switch gives us a target for future research."
Study’s finding that the loss of stress protection responsiveness in C. elegans is a result of failure to clear a single repressive chromatin modification, which interferes with a heat shock factor (HSF-1) binding event, which in turn suppresses transcription initiation in response to stress.
The molecular mechanism is particularly intriguing, as it involves a signal from germline stem cells that decreases expression of a specific demethylase enzyme, resulting in elevated levels of a repressive class of histones targeted to the genes for cell stress responses. The consequence: a rapid, coordinated inhibition of stress survival mechanisms.”
Here again we see what I pointed out in my last post Mechanism of Aging - Nature's calibration happens through tuning of activators and inhibitors.
They demonstrate that HSF1-promoter accessibility sharply declines on the second day of adulthood. This is strongly associated with sharply increased levels of H3K27me3 marks at the promoters of heat shock genes, a hallmark of transcriptional repression [that results in dysfunctional protein production]. This demonstrates, for the first time, that the repression of the heat shock response is regulated, and that epigenetic changes modulate the animals’ ability to respond to stress after reproduction onset.” “discovered that enhancing this demethylase (jmjd3.1), which is conserved to humans, prevents this decline in stress resilience, and results in animals both robust and long-lived.”
In a separate study Lead author Dr Sean Byars from the University of Melbourne says the team wanted to understand more about how CAD (coronary artery disease) has been inherited in our evolutionary past, in order to better understand why it is so common presently. "CAD is often thought of as modern disease, but actually atherosclerosis, or thickening of the artery walls, has been detected in Egyptian mummies, so we suspect it has been in our genes for thousands of years."
CAD currently affects 110 million people and causes 8.9 million deaths annually, from 2015 figures.
"According to the theory of natural selection, as proposed by Charles Darwin, genes for traits that improve individual survival or reproduction will increase or be maintained in populations, whereas those that reduce these will be selected against and gradually removed or reduced over time. "So it is unclear why CAD is so common in modern humans and this is important to understand given the global health burden it represents," explains Dr Byars.
Associate Professor Michael Inouye, who also led the study, said the findings showed that many genes associated with CAD have actually been positively selected for through evolution.
"After further research, we found CAD genes are also important for reproduction and that these genes are involved in important functions in male and female fertility being expressed in the testes, ovaries and endometrium, for example," said Assoc Prof Inouye, based at the Baker Heart and Diabetes Institute.
So in this case too same genes which were important and beneficial during reproduction biology later flip a switch and become very harmful by causing CAD – the leading killer in humans.
These studies show that for Nature once the primary function of reproduction is done the body becomes only a competition for resources for the new born and is to be bumped off. What is shocking is that aging begins its damage just after we reach reproductive maturity – puberty. By the time we begin to see the effects of this build up of damage around 50 years of age it is already too late and a lot of the damage is done. Although this shows how complex is aging disheartening the anti aging crusaders, a clue also emerges: the changes that initiate the damage are actuated by new epigenetic marks. A permanent cure for aging may lurk in the corridor of the epigenome and the transcription factors.
