Aging is Primarily Epigenetic and Reversible?

M

Mr._Clark

Audioholic Samurai
Given my modest understanding of biology, I'm not sure how significant this is, but it certainly got my attention. I'd always thought short telomeres and mutations in the DNA were the prime suspects in aging, and these changes are not reversible.

Hopefully they can figure out a way to do this that doesn't require one to turn into a young mouse (lame humor alert).

>>>The work shows that a breakdown in epigenetic information causes mice to age and that restoring the integrity of the epigenome reverses those signs of aging. . . .“We believe ours is the first study to show epigenetic change as a primary driver of aging in mammals,” said the paper’s senior author, David Sinclair, professor of genetics in the Blavatnik Institute at Harvard Medical School and co-director of the Paul F. Glenn Center for Biology of Aging Research.

The team’s extensive series of experiments provide long-awaited confirmation that DNA changes are not the only, or even the main, cause of aging. Rather, the findings show, chemical and structural changes to chromatin — the complex of DNA and proteins that forms chromosomes — fuel aging without altering the genetic code itself.<<<

 
cpp

cpp

Audioholic Ninja
Also, something which has been known for years, a change in diet and exercise can lengthen telomeres.

Maintain a healthy weight with healthy eating.
  1. Exercise regularly.
  2. Quit smoking.
  3. Get enough sleep.
  4. Reduce or manage stress.
  5. Eat a telomere-protective diet full of foods high in vitamin C, polyphenols, and anthocyanins. Consume red peppers, kale, dark chocolate, and blueberries for a positive balance that protects DNA from stress.
  6. Monitor cholesterol and sugar levels regularly to avoid the onset of diabetes or high cholesterol
Also, short telomeres is also associated with several disorders and diseases, such as dyskeratosis congenita ( bone marrow failure) , aplastic anemia ( lack of new blood cells) , pulmonary fibrosis (lung diseases) , and even cancer. I can tell you from the treatment alone from cancer impacts your well being.
 
Swerd

Swerd

Audioholic Warlord
The field of epigenetics has always been very interesting to me. In cancer treatment, it was observed that certain drugs that allowed the accumulation of acetyl groups on histone proteins (these drugs were called histone deacetylase (HDAC) inhibitors). Histone proteins bind tightly to DNA, and are associated with tightly wound DNA (chromatin) that is not actively expressed. The acetylation of histones is thought to be a reversible chemical switch – where low acetylation is associated with loosely wound chromatin and high levels of gene expression – and high acetylation is associated with tightly wound chromatin and low levels of gene expression. (This oversimplifies things, but it's good enough as a simple intro to this topic.)

I made it my business to learn as much as I could about epigenetics, a very complex topic. Let me try to define it at the simplest level. All of our cells have the same genes and chromosomes. Yet, we have many very different types of cells and tissues in our bodies. How do some cells become brain tissue, and other cells become lung, skin, bone, muscle, etc? In biology, this process is called differentiation or development. The theory has been that different genes get expressed (turned on) or silenced during different stages of development. In the field of cancer, the theory is that epigenetic changes during development & differentiation can sometimes run amok, leading to tumors where normal development had been interrupted or defective.

In the lab, these drugs could induce certain human leukemia cell lines (HL60 cells, derived from the blood of leukemia patients) to stop being cancer cells. These cells typically divide rapidly (about once every day) while growing in liquid suspension cultures. They are known to be descended from bone marrow cells, the precursors of many types of red & white blood cells. But these leukemia cells don't do any of the cell functions that you would expect of those cells. They just divide and divide.

At high enough concentrations, above 5 µM (micromolar, 5 parts per million), these drugs killed the leukemia cells. But at about 1 µM, these drugs allowed the leukemia cells to survive, but stopped their rapid cell division. They also stopped growing in liquid suspension (typical of many tumor cells), and settled onto plastic surfaces if they had been coated with certain proteins (growth while adhering to surfaces is a feature common to many non-tumor cells).

Interestingly, at the same time these HL60 cells stopped dividing and switched from growing in suspended cultures to adherent cultures, these leukemia cells also started to produce hemoglobin, a protein expressed by mature red blood cells. It was as if the treatment made the HL60 cells stop being rapidly dividing cancer cells, and acquire at least one normal function. This became known in the cancer world as "differentiation therapy", where you don't aim to burn or poison the tumor cells, but try to trick them into abandoning their worst cancer cell traits and differentiate into something more like normal cells.

I followed this field very closely as 2 or 3 generations of these histone deaceytlase inhibitor drugs were developed. The National Cancer Institute encouraged their development, and ran a number of clinical trials with them. The early forms of HDAC inhibitors weren't very potent. In the lab they worked at 1-5 millimolar concentrations (mM, 1 to 5 parts per thousand). No patient could take enough of these drugs, given IV or orally, to come close to those concentrations.

At least two of the next generation of HDAC inhibitor drugs were more potent. But it was still difficult to get enough into patients' blood stream to achieve a concentration of 1 µM. Both were approved for use in treating cutaneous T-cell lymphoma (CTCL), but in other more common forms of cancer these drugs were effective, but not effective enough for approval.

For example, clinical trials of Zolinza (an HDAC inhibitor made by Merck) were done in advanced lung cancer, multiple myeloma, and a number of other types of cancer. Zolinza was given in combination with other standard chemotherapy drugs. In the lung cancer trial, that HDAC inhibitor was combined with standard chemotherapy (carboplatin & paclitaxel), and appeared to work better than the standard chemotherapy alone. But about 40% of those patients experienced fatigue so severe that they couldn't get out of bed, often requiring hospitalization. Most of those patients quit the trial rather than go through 8 full weeks of treatment. It's been well known that carboplatin & paclitaxel treatment can temporarily stop lung tumors from growing, even shrinking them, but it requires the full 8 weeks of treatment. Combining them with an HDAC inhibitor worked well in the lab and in mice, but in humans, it caused too much fatigue. It was very frustrating for me, as this was my baby for a number of years. It was frustrating for Merck too, not to mention those lung cancer patients.

Interestingly, the whole field of epigenetics came about from scientists who studied the genetics of development in fruit flies. Typical of insects, fruit flies have 4 stages of life: eggs, larvae, pupae, and adults. These scientists used classic old-school genetic methods to identify a large number of mutations that interrupted the normal development of fruit flies between these stages. Decades later, these mutations were found to be in genes involved in the epigenetic control of gene expression during insect development. Similar genes are higher mammals, including humans. And now, they are active topics in cancer and aging research. This is a good reason why we must always fund basic science research. You never can predict where it takes you.

All this background on epigenetics is complex enough that I never read much about epigenetics with regard to aging. Once I get my hands on this paper, I'll read it with interest.

Sorry for such a long post.
 
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highfigh

highfigh

Seriously, I have no life.
Also, something which has been known for years, a change in diet and exercise can lengthen telomeres.

Maintain a healthy weight with healthy eating.
  1. Exercise regularly.
  2. Quit smoking.
  3. Get enough sleep.
  4. Reduce or manage stress.
  5. Eat a telomere-protective diet full of foods high in vitamin C, polyphenols, and anthocyanins. Consume red peppers, kale, dark chocolate, and blueberries for a positive balance that protects DNA from stress.
  6. Monitor cholesterol and sugar levels regularly to avoid the onset of diabetes or high cholesterol
Also, short telomeres is also associated with several disorders and diseases, such as dyskeratosis congenita ( bone marrow failure) , aplastic anemia ( lack of new blood cells) , pulmonary fibrosis (lung diseases) , and even cancer. I can tell you from the treatment alone from cancer impacts your well being.
Kale-

 
M

Mr._Clark

Audioholic Samurai
The field of epigenetics has always been very interesting to me. In cancer treatment, it was observed that certain drugs that allowed the accumulation of acetyl groups on histone proteins (these drugs were called histone deacetylase (HDAC) inhibitors). Histone proteins bind tightly to DNA, and are associated with tightly wound DNA (chromatin) that is not actively expressed. The acetylation of histones is thought to be a reversible chemical switch – where low acetylation is associated with loosely wound chromatin and high levels of gene expression – and high acetylation is associated with tightly wound chromatin and low levels of gene expression. (This oversimplifies things, but it's good enough as a simple intro to this topic.)

I made it my business to learn as much as I could about epigenetics, a very complex topic. Let me try to define it at the simplest level. All of our cells have the same genes and chromosomes. Yet, we have many very different types of cells and tissues in our bodies. How do some cells become brain tissue, and other cells become lung, skin, bone, muscle, etc? In biology, this process is called differentiation or development. The theory has been that different genes get expressed (turned on) or silenced during different stages of development. In the field of cancer, the theory is that epigenetic changes during development & differentiation can sometimes run amok, leading to tumors where normal development had been interrupted or defective.

In the lab, these drugs could induce certain human leukemia cell lines (HL60 cells, derived from the blood of leukemia patients) to stop being cancer cells. These cells typically divide rapidly (about once every day) while growing in liquid suspension cultures. They are known to be descended from bone marrow cells, the precursors of many types of red & white blood cells. But these leukemia cells don't do any of the cell functions that you would expect of those cells. They just divide and divide.

At high enough concentrations, above 5 µM (micromolar, 5 parts per million), these drugs killed the leukemia cells. But at about 1 µM, these drugs allowed the leukemia cells to survive, but stopped their rapid cell division. They also stopped growing in liquid suspension (typical of many tumor cells), and settled onto plastic surfaces if they had been coated with certain proteins (growth while adhering to surfaces is a feature common to many non-tumor cells).

Interestingly, at the same time these HL60 cells stopped dividing and switched from growing in suspended cultures to adherent cultures, these leukemia cells also started to produce hemoglobin, a protein expressed by mature red blood cells. It was as if the treatment made the HL60 cells stop being rapidly dividing cancer cells, and acquire at least one normal function. This became known in the cancer world as "differentiation therapy", where you don't aim to burn or poison the tumor cells, but try to trick them into abandoning their worst cancer cell traits and differentiate into something more like normal cells.

I followed this field very closely as 2 or 3 generations of these histone deaceytlase inhibitor drugs were developed. The National Cancer Institute encouraged their development, and ran a number of clinical trials with them. The early forms of HDAC inhibitors weren't very potent. In the lab they worked at 1-5 millimolar concentrations (mM, 1 to 5 parts per thousand). No patient could take enough of these drugs, given IV or orally, to come close to those concentrations.

At least two of the next generation of HDAC inhibitor drugs were more potent. But it was still difficult to get enough into patients' blood stream to achieve a concentration of 1 µM. Both were approved for use in treating cutaneous T-cell lymphoma (CTCL), but in other more common forms of cancer these drugs were effective, but not effective enough for approval.

For example, clinical trials of Zolinza (an HDAC inhibitor made by Merck) were done in advanced lung cancer, multiple myeloma, and a number of other types of cancer. Zolinza was given in combination with other standard chemotherapy drugs. In the lung cancer trial, that HDAC inhibitor was combined with standard chemotherapy (carboplatin & paclitaxel), and appeared to work better than the standard chemotherapy alone. But about 40% of those patients experienced fatigue so severe that they couldn't get out of bed, often requiring hospitalization. Most of those patients quit the trial rather than go through 8 full weeks of treatment. It's been well known that carboplatin & paclitaxel treatment can temporarily stop lung tumors from growing, even shrinking them, but it requires the full 8 weeks of treatment. Combining them with an HDAC inhibitor worked well in the lab and in mice, but in humans, it caused too much fatigue. It was very frustrating for me, as this was my baby for a number of years. It was frustrating for Merck too, not to mention those lung cancer patients.

Interestingly, the whole field of epigenetics came about from scientists who studied the genetics of development in fruit flies. Typical of insects, fruit flies have 4 stages of life: eggs, larvae, pupae, and adults. These scientists used classic old-school genetic methods to identify a large number of mutations that interrupted the normal development of fruit flies between these stages. Decades later, these mutations were found to be in genes involved in the epigenetic control of gene expression during insect development. Similar genes are higher mammals, including humans. And now, they are active topics in cancer and aging research. This is a good reason why we must always fund basic science research. You never can predict where it takes you.

All this background on epigenetics is complex enough that I never read much about epigenetics with regard to aging. Once I get my hands on this paper, I'll read it with interest.

Sorry for such a long post.
Interesting. I didn't know epigenetics is also involved in some cancers.

It's not entirely clear to me if the "aging" Sinclair induced with epigenetic changes in mice is really the same aging that occurs naturally? It seems to me he fudged around with epigentics in a way that caused "stuff" that looks like aging in mice, and then applied some anti-fudge in way that reversed the "stuff" that looks like aging. How do we know anti-fudge will work against real (natural) aging?

I realize my terminology is off, but I'm not sure of the correct way to say what I'm getting at.

Edit: My question about the efficacy of anti-fudge is rhetorical (I'm assuming there's really no way to know for sure at this point).
 
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Swerd

Swerd

Audioholic Warlord
Interesting. I didn't know epigenetics is also involved in some cancers.

It's not entirely clear to me if the "aging" Sinclair induced with epigenetic changes in mice is really the same aging that occurs naturally? It seems to me he fudged around with epigentics in a way that caused "stuff" that looks like aging in mice, and then applied some anti-fudge in way that reversed the "stuff" that looks like aging. How do we know anti-fudge will work against real (natural) aging?
Do you have a link to that recent Cell paper by Yang et al? I could get only the abstract & summary. I'd have to pay for the full text & figures. It's been 6 years since I retired, but I guess I'm still spoiled by the full online access to the NIH library I used to have.

I did find a 2019 review paper by Kane & Sinclair that seems to outline their thinking.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424622/pdf/nihms-1015538.pdf

In cancer treatment, it quickly became clear that the so-called epigenetic drugs, alone, didn't do enough to stop most advancing tumors. Studies done in some clinical trials showed that high levels of acetylation of histone proteins acetylation could be achieved without positive anti-tumor responses. Clearly, there were other targets of these drugs.

Histones are proteins in the nucleus that bind tightly to DNA. When enough of them are tightly bound to a stretch of DNA, it appears as tightly wound chromatin. But they don't always do that, they can be switched on or off of that tight binding. When fewer histones bind to DNA, it appears as diffuse or loosely wound DNA, known as hetero-chromatin. The dogma is that hetero-chromatin can be expressed as mRNA and translated into proteins, while tightly wound DNA is not expressed. Acetylation and deacetylation of histone proteins is only one of those switches.

With cancer treatment, it was found that there were also many other non-histone proteins, both inside and outside of the cell nucleus, that could be reversibly acetylated. Some of them were clearly implicated with effective anti-cancer treatments. They were discovered to be part of the extensive DNA repair system. They could repair DNA damaged by UV light or radiation, such as is used in radiation therapy of tumors. Histone deacetylase inhibitor drugs kept them more active in cancer cell lab models.

As usual in the search for effective cancer treatments, if the experimental drug or drug combinations didn't hit an immediate home run, it was abandoned by the drug companies. That's what happened with histone deacetylase inhibitors. Clearly more basic research is needed before this topic is understood well enough to use in cancer treatment. I am confident that epigenetic therapy will re-emerge in the future.
 
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