Scientists locate the protein that will extend your life and figure out how to make it last longer

Lengthening Telomere, a DNA protein, may be a key to extending life to much older than 100 years.

Telomeres are DNA-protein complexes that protect the end of human chromosomes from DNA damage or fusion with neighboring chromosomes.  Nutritionists have long been interested in the dynamics of telomere length in the human body, and how telomeres factor into human health, lengthening life expectancy, and even have pondered the possibility of Immortality.   Research is showing that certain nutrients play a huge part in protecting telomere length, ultimately determining how long you live.

“The best analogy that we have for telomeres is that they’re like the little tabs on the end of shoelaces,” says Dr Adam Rutherford, a geneticist and author of Creation: The Origin of Life.

Just as the tabs, or “aglets”, hold the strands of the laces together, he says, telomeres – repetitive stretches of DNA on the end of each chromosome – perform the same function.

“Chromosomes are made up of a double helix, two strands of DNA, and they need an endpoint,” says Rutherford. “Without telomeres they’d unravel, like two bits of string that have been tied together.”

Studies have shown that certain Vitamins contribute to the length of a Telomere.  Scientists at the European Journal of Nutrition (EJON) found that the B vitamin folate also plays an important part in maintenance of DNA integrity and DNA methylation, which in turn influence telomere length. Researchers have found that women who use vitamin B12 supplements have longer telomeres than those who don’t. Vitamin D3, zinc, iron, omega-3 fatty acids, and vitamins C and E also influence telomere length.

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Human-pig hybrid formed in the lab for the first time

Scientists have successfully created a human-pig hybrid be implanting human stem cells inside of a pig and watching them grow.  The process brings excitement to those that may need an organ transplant, as we can, very literally, grow the organs we need within a non-human animal.

The numbers tell us that a new person gets put on the list of people awaiting an organ transplant every 10 minutes and every day 22 people die without receiving the organ they need.  This process could change that intricately.

The scientists have created what’s known as a chimera: an organism that contains cells from two different species.

“In ancient civilizations, chimeras were associated with God,” says lead study author Jun Wu of the Salk Institute.  He goes on to say that our ancestors thought “the chimeric form can guard humans.”  Perhaps, with this new creation, they can.

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CRISPR pioneer muses about long journey from China to pinnacle of American science

That’s because of CRISPR, the gene-editing technique that lets scientists manipulate the genetic code of organisms almost like revising a sentence with a word processor. Zhang was one of its pioneers, and on Wednesday he emerged victorious after a bitter patent dispute.The ruling, by judges with the U.S. Patent Office, declared that Zhang’s work on living plant and animal cells was sufficiently original to deserve its own protection. It was a decisive outcome that will surely prove lucrative for Zhang and the Broad Institute, but he did not do anything special to celebrate. He made no immediate public comment. He did not even read the news coverage, he said.

“The patent stuff is not so interesting, and it can be distracting,” the soft-spoken scientist offered a day later, finally addressing the case as he sat down with a Washington Post reporter for a previously scheduled interview. “Now we can get back to work.”

The patent dispute was closely followed in the triangle of geography marked by the institute, Harvard University and the Massachusetts Institute of Technology. Here, in what has become the Silicon Valley of the life sciences, Zhang and his colleagues have spun off ventures that can commercialize their inventions.

CRISPR is an all-purpose tool that promises great advances in the prevention of diseases caused by genetic mutations. In China, Zhang’s birth country, it is already being used in human clinical trials.

Yet the technique has also raised unsettling possibilities for cosmetic human enhancements and “designer babies.” Earlier this week, the National Academy of Sciences and National Academy of Medicine produced a long report on the ethics of gene editing, arguing for extreme caution when dealing with heritable human traits but leaving open the possibility of use to remove disease-causing genes.

Some critics worry about a slippery slope, but Zhang thinks the bioethics committee got it just right.

“I think these are important issues, but I don’t think right at this second we should be overly concerned about it. It’s too far off,” he said.

The politics of science

Even with the patent case behind him, however, there is another significant distraction these days. It arises not through the courts but from the White House.

Science is inherently an international enterprise, built around a universal language of discovery and methodology. Zhang’s lab, like similar facilities across the country, has a large percentage of foreign-born scientists drawn to research opportunities in the United States.

President Trump’s executive order banning entry from seven Muslim-majority countries has alarmed this global community. The Broad, as it is commonly called, put out a statement of opposition, saying the order “turns its back on one of America’s greatest sources of strength: the flow of visitors, immigrants and refugees who have enriched our nation with their ideas, dreams, drive, energy, and entrepreneurship.”

 Zhang talks of his own life story when asked about Trump’s action.

“From my own experience, America has been an amazing place,” he said. “And it sort of gives opportunities for immigrants to realize what they want to do, to reach for their potential, and also, by doing that, make the world a better place. I’m very fortunate to have had the opportunity to move here.”

He was 11 when he first came to the United States in 1993. He spoke almost no English, arriving with his father to at last rejoin his mother. The teeming city of Shijiazhuang, in the north of China, was replaced by the alien landscape of Des Moines.

His mother had not intended to stay following her studies here, but Iowans embraced her. She got a good job with a company called the Paper Corp. She decided to start a new life and bring her son and husband to the United States. They each received a series of visas and green cards. She eventually became a citizen, as did her son. Her husband remains a Chinese citizen.

“I never felt I was discriminated against. I never felt we weren’t welcome there,” Zhang said of his youth in the heartland. And there were other immigrants, too, many of them Vietnamese refugees from war zones. He spent half the day learning English and then playing word bingo to hone his vocabulary.

He hung out with other kids interested in science. “We were all nerds,” he said. As a teenager, he got a position working after school at the Human Gene Therapy Research Institute. He could call himself a bench scientist, often working late into the evening while his mother waited for him in the parking lot.

Elite institutions soon recognized his brilliance. His résumé includes a degree from Harvard, then a doctorate from Stanford. He learned about the natural bacterial immune system, CRISPR, an acronym for clustered regularly interspaced short palindromic repeats.

Bacteria evolved a defense mechanism against viral invaders that would insert genetic material into bacterial DNA. The system functions like molecular scissors, snipping away the invasive material.

Two other researchers, who would become rivals in the patent case, published the first paper describing the gene-editing technique and applied for patents. Jennifer Doudna and Emmanuelle Charpentier showed how to turn the natural bacterial system into a laboratory tool, but initially they did not apply it to plant and animal cells. That was Zhang’s breakthrough, published in 2013 at the same time as a similar paper by Harvard geneticist George Church.

“Feng was very early in recognizing the importance of reducing it to practice in mammalian cells,” Church said this week.

Doudna and Charpentier can still receive patents on their original discovery. In an email Friday to The Post, Doudna wrote, “Obviously the Broad Institute is happy that their patent didn’t get thrown out, but we are pleased that our patent can now proceed to be issued.”

But she raised another concern. The judges’ decision was based in part on public comments she made, expressing uncertainty about whether CRISPR would work in cells with nuclei. Because of that, she fears the ruling could have a chilling effect on scientific communication.

“Must every scientist now factor in a potential patenting strategy and alter how transparent they are about their work?” Doudna wrote.

Doudna and Charpentier have already received the $3 million Breakthrough Prize funded by Silicon Valley tech tycoons. Then earlier this year they won the Japan Prize, each receiving the equivalent of about $420,000.

And lurking out there somewhere is the Nobel.

‘Why do we age?’

On Thursday, the morning after the ruling, Zhang drove his 2004 BMW to work as always, arriving at 7:30 to meet with a student and help him prepare for a class presentation. Then he had a call with an oil executive in the United Arab Emirates who is funding research on a genetic disease that affects the executive’s daughter.

He still has a spot in his lab for experiments, though he does those during the summer since right now he’s busy teaching two classes. The lab work is in the hands of about 20 researchers, some already with doctorates and medical degrees.

CRISPR gets all the publicity these days, but it is not the only game in town. Life is a complex chemical system that over billions of years has developed all sorts of tricks and mechanisms. Most of the microbes in the human gut have never been cultured or characterized. Basic questions remain unanswered.

“Why do we age?” Zhang asked.

The CRISPR system is itself a work in progress. It’s an inexact editor still.

“It cuts very well,” he said. “To insert something, it doesn’t work very well at all.”

But he’s working on that. Everyone stand by.

A new CRISPR breakthrough could lead to simpler, cheaper disease diagnosis

Scientists say SHERLOCK is a ‘game changer’

Scientists say SHERLOCK, a new CRISPR breakthrough and diagnosis tool, could be a game changer for the ability to identify infectious diseases like Zika.

The controversial laboratory tool known as CRISPR may have found a whole new world to conquer. Already the favored method of editing genes, CRISPR could soon become a low-cost diagnostic tool that could be used practically anywhere to determine if someone has an infectious disease such as Zika or dengue.

CRISPR — which stands for Clustered Regularly Interspaced Short Palindromic Repeats — is basically a bacterial immune system that uses “molecular scissors” to snip away genetic material from invasive viruses. Early in this decade, researchers figured out how to exploit the natural system to craft a relatively cheap, remarkably easy-to-use technology for editing genetic codes almost as readily as using a word processor to revise a paragraph.

On Thursday, Feng Zhang, one of the pioneers of CRISPR, and 18 colleagues published a paper in the journal Science showing how they had turned this system into an inexpensive, reliable diagnostic tool for detecting nucleic acids — molecules present in an organism’s genetic code — from disease-causing pathogens. The new tool could be widely applied to detect not only viral and bacterial diseases but also potentially for finding cancer-causing mutations.

CRISPR has been a sensation in the world of molecular biology, but the powerful tool has incited fears that it could be misused. Ethicists earlier this year released a report saying it should be limited in humans to treating diseases or disabilities, and with special caution when genetic changes would involve eggs, sperm or embryos and potentially be inherited by future generations. But CRISPR is already widely used in laboratory studies and has shown great promise in revealing the genetic origins of diseases, including cancer. This new application would propel CRISPR into the much less controversial realm of point-of-care disease diagnosis.

The new study has a whiff of marketing about it: Zhang and his colleagues have named their new tool SHERLOCK — for Specific High Sensitivity Enzymatic Reporter UnLOCKing.

“Nature is really amazing. Over the course of billions of years, it’s come up with all these very powerful enzyme systems, and by studying the basic biology of these systems, some of them will give rise to important applications — like genome editing, like diagnostics,” Zhang, of the Broad Institute of MIT and Harvard, told The Washington Post.

Co-author Jim Collins, also of the Broad Institute, said, “In this diagnostic application we are really harnessing the power and diversity of biology. … I view it as a potentially transformative diagnostic platform.”

They report that their technique is highly portable and could cost as little as 61 cents per test in the field. Such a process would be extremely useful in remote places without reliable electricity or easy access to a modern diagnostic laboratory.

“We showed that this system is very stable, so you can really put it on a piece of paper and it will survive. You don’t have to refrigerate it all the time,” Zhang said.

“My head is spinning a little bit because this looks very, very provocative. And exciting,” said William Schaffner, a professor of infectious diseases and preventive medicine at Vanderbilt University Medical Center, who was not involved in the new research. “If you had something that could be used as a screening test, very inexpensively and rapidly, that would be a huge advance, particularly if it could detect an array of infectious agents.”

Collins said the scientists behind SHERLOCK have filed for patents on the technology, and are discussing ways to move their new tool from the laboratory to the clinical arena.

Zhang is one of the key figures in the CRISPR patent fight between the Broad Institute and the University of California at Berkeley, the latter the homebase of CRISPR pioneer Jennifer Doudna. The patent board ruled in favor of Zhang and Broad earlier this year. Doudna and another researcher had published their CRISPR discoveries first, but Zhang took the technique another step, into cells with nuclei, and the patent board ruled that the second step was sufficiently different that both could be eligible for patent protection. On Thursday, Berkeley and other interested parties filed an appeal of that ruling.

Scott Weaver, an infectious disease researcher at the University of Texas Medical Branch at Galveston, who was not involved in the new research, said after reading the study, “It looks like one significant step on the pathway which is the Holy Grail, which is developing point-of-care, or bedside detection, which doesn’t require expensive equipment or even reliable power.”

Harvard geneticist George Church is one of the lead researchers propelling CRISPR, a breakthrough gene-editing technique, into the future.
CRISPR is capable of preventing congenital disease.

CRISPR Gene Editing Has Been Used to Cure Mice of Sickle Cell Disease

  • The results are promising and could lead to a treatment for this disease that afflicts about 100,000 Americans.
  • While human tests are still a ways off, CRISPR could one day be used to effectively treat a number of ailments, from high cholesterol to HIV.


Gene editing shows promise as a new treatment for sickle cell disease, according to a study published in the online journal Science Translational Medicine.

Experts from the University of California, Berkeley, UCSF Benioff Children’s Hospital Oakland Research Institute (CHORI), and the University of Utah School of Medicine have found success in correcting the blood cell mutation in tests of the blood of both mice and human sickle cell patients using CRISPR-Cas9, a genome “scissor” that can cut out and edit a DNA sequence.

After CRISPR was used to correct the mutated hematopoietic stem cells — precursor cells that mature into the hook-shaped hemoglobin characteristic of sickle cell disease, the corrected blood stem cells produced healthy hemoglobin. Following reintroduction into the mice, the genetically engineered stem cells remained in circulation for at least four months — a significant indication that any potential therapy would be lasting.

 The tests of blood from afflicted humans showed that the proportion of corrected stem cells was high enough to produce substantial benefit for the patients, so the researchers are hoping to one day be able to reinfuse the human patients with the edited strain of cells as it could alleviate symptoms of sickle cell disease, including anemia and pain caused by vessel blockages.

While the results are promising and could lead to a treatment for this disease that afflicts about 100,000 Americans, the researchers emphasize that future testing on mice and safety analyses would need to be conducted before human trials could begin.


“Sickle cell disease is just one of many blood disorders caused by a single mutation in the genome,” said Jacob Corn, senior author on the study. “It’s very possible that other researchers and clinicians could use this type of gene editing to explore ways to cure a large number of diseases.”

Indeed, developments in gene-editing  technology within such fields as medicine, agriculture, and biology are taking us further into what some are calling “the age of CRISPR.”

It’s already being researched as a treatment for many other ailments and disorders— β-thalassemia, severe combined immunodeficiency (SCID)Wiskott-Aldrich syndrome, even HIV — so this one type of technology could end up being something of a panacea for what ails us, as long as what ails us is genetic.

CRISPR Gene-Editing Tool May Help Improve Cancer Immunotherapy.

Using a new tool for editing genomes, known as CRISPR, researchers have genetically engineered immune cells and improved the ability of these cells to kill cancer cells in mice.

The cells were modified to express proteins on their surfaces called chimeric antigen receptors (CARs), which enabled the cells to recognize and attack cancer cells that expressed the corresponding antigen.

Mesothelin-specific CAR T cells attacking a cancer cell.

In experiments with the mice, immune cells that had been engineered to express CARs using CRISPR were more effective at killing tumor cells than immune cells engineered using conventional methods, the researchers reported in Nature on February 22.

The type of immunotherapy evaluated in the study is CAR T-cell therapy, a form of adoptive cell transfer. With this treatment, a patient’s own T cells, a type of immune cell, are collected from blood, modified genetically to make them better at attacking tumor cells, expanded in the laboratory, and finally returned to the patient.

To explore ways to enhance the effectiveness of CAR T-cell therapies, Michel Sadelain, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center, and his colleagues turned to a technique called CRISPR, which allows researchers to edit genomes with more speed and precision than other approaches.

Creating More Potent T Cells

Conventional approaches for engineering T cells to express a CAR, such as using a retrovirus to deliver the gene, result in the gene being inserted at random locations in the genome.

With these approaches, however, there is a chance that the CAR gene could insert itself in a way that disrupts the normal functioning of the genome, causing unintended consequences, the study authors noted.

By contrast, the CRISPR/Cas9 system allows for the specific placement of genes. Dr. Sadelain and his colleagues used CRISPR to deliver a CAR gene to a precise location in the T-cell genome: the T-cell receptor alpha chain (TRAC) gene.

The TRAC region of the genome includes the gene for the T-cell receptor, which helps the immune cell detect foreign molecules. The CRISPR system edits out part of the TRAC gene in the T cells, allowing the CAR gene to insert there.

When the researchers tested the two kinds of CAR T cells in mouse models of leukemia, those in which the CAR gene had been inserted at the TRAC locus via CRISPR were more effective at destroying tumor cells than those in which it was inserted randomly with a retrovirus.

Experiments suggested that the improved anti-tumor responses of cells engineered using CRISPR was the result, in part, of the “highly regulated CAR expression” in these T cells, noted Dr. Sadelain.

Overcoming “Exhaustion”

In addition, the CAR T cells created with CRISPR were less likely to stop recognizing and attacking tumor cells after a certain time point, a phenomenon researchers call “exhaustion.”

“We found that the level of CAR expression [on T cells] and the dynamic response of the CAR following the recognition of antigens are critical in determining whether exhaustion will occur rapidly,” explained Dr. Sadelain. “Expressing the CAR from the TRAC locus greatly diminished exhaustion, resulting in superior tumor eradication.”

Based on three measures of exhaustion, less than 2% of CRISPR-created T cells showed signs of exhaustion, compared with up to half of conventionally engineered CAR T cells.

“This report describing the use of CRISPR/Cas9 technology to insert a CAR gene into a specific location in the genome is an important advance for the CAR field,” said James N. Kochenderfer, M.D., who develops and tests T-cell therapies in NCI’s Center for Cancer Research (CCR) and was not involved in the study.

“The finding that the location of CAR gene insertion can affect T-cell function is particularly intriguing,” Dr. Kochenderfer continued. “New gene-editing technologies will likely lead to rapid improvement in antigen-targeted T-cell immunotherapies for cancer.”

Looking Ahead

In an accompanying editorial, Marcela V. Maus, M.D., Ph.D., of Harvard Medical School identified three important improvements that CRISPR could potentially bring to T-cell-based therapies, one being more-effective tumor responses.

Second, the targeted nature of CRISPR-mediated CAR integration into the genome might “prove safer than random integration, which carries the potential risk of generating a harmful mutation,” Dr. Maus wrote.

Finally, this approach might “enable off-the-shelf CAR T cells to be made that need not come from a patient’s own T cells,” she continued. “This would enable easier and cheaper manufacture of CAR T cells.”

At Memorial Sloan Kettering, Dr. Sadelain’s team has been modifying its manufacturing techniques to prepare for clinical testing in the future. The researchers believe their findings could have implications for research on diseases other than cancer.

“The biology of CARs still has many secrets and surprises to reveal,” Dr. Sadelain said, adding: “Research on CARs will lead to more effective and safer therapies for a number of diseases.”

Critical step in DNA repair, cellular aging pinpointed

The body’s ability to repair DNA damage declines with age, which causes gradual cell demise, overall bodily degeneration and greater susceptibility to cancer. Now, research reveals a critical step in a molecular chain of events that allows cells to mend their broken DNA.

The body’s ability to repair DNA damage declines with age, which causes gradual cell demise, overall bodily degeneration and greater susceptibility to cancer.

DNA repair is essential for cell vitality, cell survival and cancer prevention, yet cells’ ability to patch up damaged DNA declines with age for reasons not fully understood.

Now, research led by scientists at Harvard Medical School reveals a critical step in a molecular chain of events that allows cells to mend their broken DNA.

The findings, published March 24 in Science, offer a critical insight into how and why the body’s ability to fix DNA dwindles over time and point to a previously unknown role for the signaling molecule NAD as a key regulator of protein-to-protein interactions in DNA repair. NAD, identified a century ago, is already known for its role as a controller of cell-damaging oxidation.

Additionally, experiments conducted in mice show that treatment with the NAD precursor NMN mitigates age-related DNA damage and wards off DNA damage from radiation exposure.

The scientists caution that the effects of many therapeutic substances are often profoundly different in mice and humans owing to critical differences in biology. However, if affirmed in further animal studies and in humans, the findings can help pave the way to therapies that prevent DNA damage associated with aging and with cancer treatments that involve radiation exposure and some types of chemotherapy, which along with killing tumors can cause considerable DNA damage in healthy cells. Human trials with NMN are expected to begin within six months, the researchers said.

“Our results unveil a key mechanism in cellular degeneration and aging but beyond that they point to a therapeutic avenue to halt and reverse age-related and radiation-induced DNA damage,” said senior author David Sinclair, professor in the Department of Genetics at HMS and professor at the University of New South Wales School of Medicine in Sydney, Australia.

A previous study led by Sinclair showed that NMN reversed muscle aging in mice.

A plot with many characters

The investigators started by looking at a cast of proteins and molecules suspected to play a part in the cellular aging process. Some of them were well-known characters, others more enigmatic figures.

The researchers already knew that NAD, which declines steadily with age, boosts the activity of the SIRT1 protein, which delays aging and extends life in yeast, flies and mice. Both SIRT1 and PARP1, a protein known to control DNA repair, consume NAD in their work.

Another protein DBC1, one of the most abundant proteins in humans and found across life forms from bacteria to plants and animals, was a far murkier presence. Because DBC1 was previously shown to inhibit vitality-boosting SIRT1, the researchers suspected DBC1 may also somehow interact with PARP1, given the similar roles PARP1 and SIRT1 play.

“We thought if there is a connection between SIRT1 and DBC1, on one hand, and between SIRT1 and PARP1 on the other, then maybe PARP1 and DBC1 were also engaged in some sort of intracellular game,” said Jun Li, first author on the study and a research fellow in the Department of Genetics at HMS.

They were.

To get a better sense of the chemical relationship among the three proteins, the scientists measured the molecular markers of protein-to-protein interaction inside human kidney cells. DBC1 and PARP1 bound powerfully to each other. However, when NAD levels increased, that bond was disrupted. The more NAD present inside cells, the fewer molecular bonds PARP1 and DBC1 could form. When researchers inhibited NAD, the number of PARP1-DBC1 bonds went up. In other words, when NAD is plentiful, it prevents DBC1 from binding to PARP1 and meddling with its ability to mend damaged DNA.

What this suggests, the researchers said, is that as NAD declines with age, fewer and fewer NAD molecules are around to stop the harmful interaction between DBC1 and 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.

Averting mischief

Next, to understand how exactly NAD prevents DBC1 from binding to PARP1, the team homed in on a region of DBC1 known as NHD, a pocket-like structure found in some 80,000 proteins across life forms and species whose function has eluded scientists. The team’s experiments showed that NHD is an NAD binding site and that in DBC1, NAD blocks this specific region to prevent DBC1 from locking in with PARP1 and interfering with DNA repair.

And, Sinclair added, since NHD is so common across species, the finding suggests that by binding to it, NAD may play a similar role averting harmful protein interactions across many species to control DNA repair and other cell survival processes.

To determine how the proteins interacted beyond the lab dish and in living organisms, the researchers treated young and old mice with the NAD precursor NMN, which makes up half of an NAD molecule. NAD is too large to cross the cell membrane, but NMN can easily slip across it. Once inside the cell, NMN binds to another NMN molecule to form NAD.

As expected, old mice had lower levels of NAD in their livers, lower levels of PARP1 and a greater number of PARP1 with DBC1 stuck to their backs.

However, after receiving NMN with their drinking water for a week, old mice showed marked differences both in NAD levels and PARP1 activity. NAD levels in the livers of old mice shot up to levels similar to those seen in younger mice. The cells of mice treated with NMN also showed increased PARP1 activity and fewer PARP1 and DBC1 molecules binding together. The animals also showed a decline in molecular markers that signal DNA damage.

In a final step, scientists exposed mice to DNA-damaging radiation. Cells of animals pre-treated with NMN showed lower levels of DNA damage. Such mice also didn’t exhibit the typical radiation-induced aberrations in blood counts, such as altered white cell counts and changes in lymphocyte and hemoglobin levels. The protective effect was seen even in mice treated with NMN after radiation exposure.

Taken together, the results shed light on the mechanism behind cellular demise induced by DNA damage. They also suggest that restoring NAD levels by NMN treatment should be explored further as a possible therapy to avert the unwanted side effects of environmental radiation, as well as radiation exposure from cancer treatments.

In December 2016, a collaborative project between the Sinclair Lab and Liberty Biosecurity became a national winner in NASA’s iTech competition for their concept of using NAD-boosting molecules as a potential treatment in cosmic radiation exposure during space missions.

Scientists Reverse DNA Damage in Mice. Human Trials are Next. 

DNA is a critical part of the cell, it is the instruction manual for building cells. Whilst DNA is well protected within the cell nucleus damage does occur, therefore DNA repair is absolutely essential for cell function, cell survival and the prevention of cancer. The good news is cells are able to repair damaged DNA but the bad news is that this ability declines with aging for reasons as yet to be fully understood.

An exciting new study by researchers led by Dr. David Sinclair at Harvard Medical School shows a part of the process that enables cells to repair damaged DNA involving the signalling molecule NAD. This offers insight into how the body repairs DNA and why that repair system declines as we age. Before we get into the new research study let’s take a look at how DNA damage relates to aging and what NAD is.

Genomic instability a driver of aging?

The stability and integrity of our DNA is challenged on a daily basis by various external physical, chemical and biological agents as well as by internal threats such as replication errors, reactive oxygen species and other factors.

Some aging theories such as the Hallmarks of aging implicate DNA damage as one of the primary driving processes of aging contributing to genomic instability[1]. Various premature aging diseases such as progeria are the consequence of accumulated DNA damage, however the relationship between progeria and normal aging is as yet unresolved. This is partly due to the fact that the different progeroid syndromes only manifest certain aspects of aging seen in normally aging people.

This means that this new study is very important in helping us to understand the relationship between DNA damage and aging.

What is NAD?

Nicotinamide adenine dinucleotide (NAD) is a dinucleotide, meaning that it consists of two nucleotides joined by their phosphate groups. One nucleotide contains an adenine base and the other contains nicotinamide. NAD is found in two forms, an oxidized and reduced form abbreviated as NAD+ and NADH respectively. As part of its role in metabolism, nicotinamide adenine dinucleotide supports redox reactions, the moving of electrons from one reaction to another. The transfer of electrons is the primary function of NAD but it has other roles too.

Found in every cell in our body, NAD helps to suppress genes that accelerate the aging process and is a fundamental part of our metabolic system. NAD is associated with the sirtuins, which are closely linked to longevity in mammals and other organisms. Its control over cell damaging oxidation is also well documented. NAD declines during the aging process due to being actively destroyed by inflammatory signalling as shown in a 2013 study by Schultz and Sinclair[2].

So what’s the big news?

This new study demonstrates a previously unknown role for the NAD signalling molecule as a master regulator of protein to protein interaction during DNA repair. It also gives us valuable insight into why the body’s ability to repair DNA damage begins to fail as we age[3].

These experiments conducted in mice demonstrate that treatment with a NAD precursor known as nicotinamide mononucleotide (NMN) can mitigate and resist age-related DNA damage as well as the damage resulting from exposure to radiation. Whilst there is no guarantee that these results will translate from mice to humans due to differences in biology, if they do it is of great interest.

Building on previous research

David Sinclair and his team already demonstrated that NMN can extend the lifespan of mice in a previous study[4] and reverses loss of mitochondrial function with age[5]. The team began this new study by examining the various proteins and molecules they believed were involved in the aging process.

They knew that NAD, whose levels fall with age, increases the activity of the SIRT1 protein (one of the Sirtuin family) and can delay some aspects of aging, extending the lifespan in yeast, flies and mice. They also knew that SIRT1 and PARP1, a protein that is involved in DNA repair, both consume NAD during their activation.

The team also looked at a protein called DBC1, a common protein found in humans and many other organisms from bacteria upwards. Studies had shown that DBC1 was able to inhibit the activity of SIRT1, so they believed it might also influence PARP1 given their similar roles, and wanted to see if it was connected to NAD. It turns out they were correct and the study revealed this link.

The research group tested the relationship between the three proteins by measuring protein-to-proteins interaction within human kidney cells. They discovered that PARP1 and DBC1 actually bond strongly to each other but, when NAD levels increase that bonding is reduced. Simply put, the more NAD in a cell the fewer bonds DCB1 and PARP1 can form, freeing up PARP1 so it can repair damaged DNA. They also took this further, inhibited NAD and noted the number of DBC1 to PARP1 bonds increased. This shows that reduced levels of NAD strongly influence the ability of cells to repair DNA damage.

These findings suggest that as NAD falls during the aging process the less NAD there is to prevent DBC1 and PARP1 bonding, which is harmful to DNA repair. The result of this ultimately causes DNA damage to go unrepaired and accumulate over time, leading to cell damage, mutations, loss of tissue, cell function, and organ failure.

Getting down to the nitty gritty

That in itself was interesting enough to have discovered this previously unknown function of NAD, but the researchers wanted to understand exactly how NAD was doing this. To find out how NAD prevents DBC1 from bonding with PARP1 they examined a region of DBC1 known as NHD. NHD is a pocket shaped structure common to around 80,000 different proteins in a huge number of species, and its function has been a mystery to scientists. The team showed that this NHD region is a NAD binding site and in DBC1, NAD binds to this region and prevents DBC1 from bonding with PARP1 to prevent DNA repair.

Interestingly NHD is so common in across species it suggests that this NAD binding may play a similar role preventing harmful protein interactions in many species including humans.

Moving to mice

Next the researchers treated old mice with NMN, but before they did they checked the protein levels in the mice. As predicted the old mice had lower levels of NAD in their livers, as well as lower PARP1 levels and a larger number of bonded PARP1 and DBC1 proteins. However once given NMN in their drinking water for just one week, the old mice showed significant improvement in NAD and PARP1 levels. Tests showed the NAD levels in the livers of the old mice increased similar to those observed in younger mice. PARP1 levels were a similar story and PARP1 and DBC1 bonded proteins were reduced. The researchers also recorded a reduction in biomarkers for DNA damage suggesting that DNA repair had been improved.

Finally the researchers exposed mice to radiation to damage their DNA. They discovered that mice treated with NMN before radiation exposure showed lower levels of DNA damage. The mice also did not display the characteristic changes to blood counts, such as changes to lymphocyte and hemoglobin levels typically seen after radiation exposure. Interestingly, mice treated post radiation also enjoyed similar protective effects from NMN treatment.

Of mice and men

Human trials with NMN are anticipated to begin within the next six months according to researchers and the potential discoveries are significant for our understanding of the biology of aging.

In conclusion the results show the mechanism behind DNA repair and cell death caused by DNA damage. Should further animal studies and human clinical results confirm the findings, this may pave the way for therapies that repair DNA damage due to radiation exposure from sources such as radiotherapy and environment and of course, for treating age-related decline.



[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.
[2] Schultz, M. B., & Sinclair, D. A. (2016). Why NAD+ Declines during Aging: It’s Destroyed. Cell metabolism, 23(6), 965-966.
[3] Li, J., Bonkowski, M. S., Moniot, S., Zhang, D., Hubbard, B. P., Ling, A. J., … & Aravind, L. (2017). A conserved NAD+ binding pocket that regulates protein-protein interactions during aging. Science, 355(6331), 1312-1317.
[4] North, B. J., Rosenberg, M. A., Jeganathan, K. B., Hafner, A. V., Michan, S., Dai, J., … & van Deursen, J. M. (2014). SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. The EMBO journal, e201386907.
[5] Gomes, A. P., Price, N. L., Ling, A. J., Moslehi, J. J., Montgomery, M. K., Rajman, L., … & Mercken, E. M. (2013). Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell, 155(7), 1624-1638.


Scientists Hack a Human Cell and Reprogram It Like a Computer.


Scientists Have Figured out How Life Is Able to Survive

  • A new sequencing technique that maps out and analyzes DNA damage demonstrates how bacterial cells function in two critical excision repair proteins.
  • The team’s research and discovery not only heralds the use of this new mapping technique, it could also pave the way for a solution that will help address antibiotic resistance.


Every day, the DNA in our cells gets damaged. This might sound scary, but it’s actually a normal occurrence – which makes DNA’s ability to repair itself vital to our survival. Now, scientists are beginning to better understand exactly how these repairs happen. A new sequencing technique that maps out and analyzes DNA damage demonstrates how bacterial cells function in two critical excision repair proteins: Mfd and UvrD.

The process, called nucleotide excision repair, has been used by a team from the UNC School of Medicine to gain a deeper insight into the key molecular functions of these repair systems, including the proteins’ roles in living cells. This repair process is known for fixing a common form of DNA damage called the “bulky adduct,” where a toxin or ultraviolet (UV) radiation chemically modifies the DNA.

The technique, called XR-seq lets the scientists isolate and sequence sections of DNA with the bulky adduct, thus allowing them to identify its actual locations in the genome. It has previously been used to generate a UV repair map of the human genome, as well as a map for the anticancer cisplatin drug.

For this study, scientists used the same method to repair damage caused by E. coli. As co-author of the study, Christopher P. Selby, PhD explained:

When the DNA of a bacterial gene is being transcribed into RNA, and the molecular machinery of transcription gets stuck at a bulky adduct, Mfd appears on the scene, recruits other repair proteins that snip away the damaged section of DNA, and “un-sticks” the transcription machinery so that it can resume its work. This Mfd-guided process is called transcription-coupled repair, and it accounts for a much higher rate of excision repair on strands of DNA that are being actively transcribed.


Chris Selby, PhD; Aziz Sancar, MD, PhD; and Ogun Adebali, PhD

In further experiments, the researchers defined the role of an accessory excision repair protein in E. coli – UvrD, which helps clear away each excised segment of damaged DNA. Essentially, think of Mfd as the DNA “un-sticker” and UvrD as the “unwinder.” Using the XR-seq method, scientists discovered evidence of transcription-coupled repair in normal cells, but not in cells without Mfd—implying that the protein played a key role in its repair process.

The team’s research and discovery not only heralds the use of this new mapping technique, it could also pave the way for a solution that will help address the pressing, global threat of antibiotic resistance.

“If we fail to address this problem quickly and comprehensively, antimicrobial resistance will make providing high quality universal health coverage more difficult, if not impossible,” the UN Secretary-General Ban Ki-moon said. “[Antibiotic resistance] a fundamental, long-term threat to human health, sustainable food production and development.”

To support their current research, the team now plans to study XR-seq in bacterial, human and mammalian cells, to better understand the excision repair process.

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