Dr Bryant Villeponteau the formulator of Stem Cell 100 and other Life Code nutraceuticals was recently interviewed by Dr Mercola who owns the largest health web site on the internet. Dr. Villeponteau is also the author of Decoding Longevity an new book which will be released during December. He is a leading researcher in novel anti-aging therapies involving stem cells an area in which he has been a pioneer for over three decades.
Stem cell technology could have a dramatic influence on our ability to live longer and replace some of our failing parts, which is the inevitable result of the aging process. With an interest in aging and longevity, Dr. Villeponteau started out by studying developmental biology. “If we could understand development, we could understand aging,” he says. Later, his interest turned more toward the gene regulation aspects. While working as a professor at the University of Michigan at the Institute of Gerontology, he received, and accepted, a job offer from Geron Corporation—a Bay Area startup, in the early ‘90s.
“They were working on telomerase, which I was pretty excited about at the time. I joined them when they first started,” he says. “We had an all-out engagement there to clone human telomerase. It had been cloned in other animals but not in humans or mammals.”
If you were to unravel the tip of the chromosome, a telomere is about 15,000 bases long at the moment of conception in the womb. Immediately after conception, your cells begin to divide, and your telomeres begin to shorten each time the cell divides. Once your telomeres have been reduced to about 5,000 bases, you essentially die of old age.
“What you have to know about telomerase is that it’s only on in embryonic cells. In adult cells, it’s totally, for the most part, turned off, with the exception of adult stem cells,” Dr. Villeponteau explains. “Adult stem cells have some telomerase – not full and not like the embryonic stem cells, but they do have some telomerase activity.”
Most of the research currently being done, both in academia and industrial labs, revolves around either embryonic stem cells, or a second type called induced pluripotent stem cells (iPS). Dr. Villeponteau, on the other hand, believes adult stem cells are the easiest and most efficient way to achieve results.
That said, adult stem cells do have their drawbacks. While they’re your own cells, which eliminates the problem of immune-related issues, there’s just not enough of them. Especially as you get older, there are fewer and fewer adult stem cells, and they tend to become increasingly dysfunctional too. Yet another hurdle is that they don’t form the tissues that they need to form…
To solve such issues, Dr. Villeponteau has created a company with the technology and expertise to amplify your adult stem cells a million-fold or more, while still maintaining their ability to differentiate all the different cell types, and without causing the cells to age. Again, it is the adult stem cell’s ability to potentially cure, or at least ameliorate, many of our age-related diseases by regenerating tissue that makes this field so exciting.
Dr Villeponteau believes you can add many years, likely decades, to your life simply by eating right, exercising (which promotes the production of muscle stem cells, by the way) and living an otherwise clean and healthy lifestyle. Extreme life extension, on the other hand, is a different matter.
His book, Decoding Longevity, covers preventive strategies to prolong your life, mainly diet, exercise, and supplements. A portion of the book also covers future developments in the area of more radical life extension, such as stem cell technology.
Now researchers have found a way not just to stop, but, reverse the aging process. The key is something called a telomere. We all have them. They are the tips or caps of your chromosomes. They are long and stable in young adults, but, as we age they become shorter, damaged and frayed. When they stop working we start aging and experience things like hearing and memory loss.
In a recent study published in the peer reviewed journal Nature scientists took mice that were prematurely aged to the equivalent of 80-year-old humans, added an enzyme and essentially turned their telomeres back on. After the treatment they were the physiological equivalent of young adults. You can see the before and after pictures in the videos above. Brain function improved, their fertility was restored it was a remarkable reversal of the aging process. In the top video the untreated mouse shows bad skin, gray hair and it is balding. The mouse with it’s telomeres switched back on has a dark coat color, the hair is restored and the coat has a nice healthy sheen to it. Even more dramatic is the change in brain size. Before treatment the aged mice had 75% of a normal size brain like a patient with severe Alzheimers. After the telomeres were reactivated the brain returned to normal size. As for humans while it is just one factor scientists say the longer the telomeres the better the chances for a more graceful aging.
The formal study Telomere dysfunction induces metabolic and mitochondrial compromise was published in Nature.
Additional information published by Harvard can be found in the following articles.
While scientists are not yet able to accomplish the same results in humans we believe we have developed a nutraceutical to help prolong youth and possibly extend life until age reversal therapy for humans becomes available.
New evidence that adult stem cells are critical to human aging has recently been published on a study done on a super-centenarian woman that lived to be 115 years. At death, her circulating stem cell pool had declined to just two active stem cells from stem cell counts that are typically more than a thousand in younger adults. Super-centenarians have survived all the normal diseases that kill 99.9% of us before 100 years of age, so it has been a mystery as to what actually kills these hardy individuals. This recent data suggest that stem cell decline may be the main contributor to aging. If so, stabilizing stem cells may be the best thing one can do to slow your rate of aging.
There are many theories of aging that have been proposed. For example, damage to cells and tissues from oxidative stress has been one of the most popular fundamental theories of aging for more than half a century. Yet antioxidant substances or genes that code antioxidant enzymes have proven largely ineffective in slowing aging when tested in model animals. Thus, interest by scientists has shifted to other hypotheses that might provide a better explanation for the slow declines in function with age.
Stem cells provide one such promising mechanism of aging. Of course, we all know that babies are young and vigorous, independent of the age of their parents. This is because adults have embryonic stem cells that can generate young new cells needed to form a complete young baby. Indeed, these embryonic stem cells are the product of continuously evolving stem cell populations that go back to the beginning of life on earth over 3.5 billion years ago!
In adults, the mostly immortal embryonic stem cells give rise to mortal adult stem cells in all the tissues of the body. These adult stem cells can regenerate your cells and tissues as they wear out and need replacement. Unfortunate, adult stem cells also age, which leads to fewer cells and/or loss of function in cell replacement. As functional stem cells decline, skin and organs decline with age.
The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes. The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.
Humanity has long been in search of the mythical Fountain of Youth, from Alexander the Great to knights of the Crusades.
But now Silicon Valley scientists believe they are on the cusp of discovering the cause of aging, which will help them achieve the unthinkable: find a cure.
Earlier this year, doctor and investor Joon Yun launched the Palo Alto Longevity Prize, offering $1 million (£650,000) to anyone who could “hack the code of life” and come up with a way to keep us young.
“It’s always been said that there’s two certainties in life: death and taxation, but death isn’t looking so certain anymore,” says Stuart Kim, one of 50 world-class advisers on the prize board and a professor in Developmental Biology and Genetics at Stanford University.
He believes aging is simply a medical problem for which a solution can be found.
The prize will be awarded to the first team to unlock what many believe to be the secret to aging: homeostatic capacity, or the ability of the body’s systems to stabilise in response to stressors.
As the body ages, being able to recover from diseases, injuries and lifestyle stresses becomes more difficult. In youth, blood pressure and elevated blood sugar levels can return easily to normal levels.
As homeostatic capacity erodes as we get older, the body is no longer able to regulate these changes as effectively, resulting in diseases such as diabetes or hypertension.
Dr Yun, who worked for several years as a radiologist at Stanford Hospital before joining a hedge fund investing in health care, uses the analogy of a “weeble wobble” toy to explain that no matter how far it is pushed, it is able to centre itself again.
A person only becomes aware of their body’s homeostasis when they start losing it in middle age: often characterised by the loss of ability to tolerate cold or hot weather, or feeling nauseous after a roller-coaster ride where you once felt exhilarated.
“Up until about 45 years old, most people die from external stressors such as trauma or infection, but as we get older we die of what looks like a loss of intrinsic capacities,” he tells The Sunday Telegraph.
Increased homeostatic capacity could allow people to live beyond 120 years – the theoretical maximum human lifespan.
Scientists could effectively slow down the body’s clock and enable us to remain middle aged for 50 years or more, meaning we can feel 50 when we are really 80. The future could see us not just living longer, but staying healthier for longer.
“This isn’t like plastic surgery where you’re papering over the cracks, this is actually making a person younger from the inside out,” Dr Yun says.
The first half of the prize will be awarded next year to the team that can restore the homeostatic capacity of an aging adult mammal to that of a young one, thereby reversing the effects of aging.
The second half to the team that can then extend the lifespan of their chosen mammal by 50 per cent of published norms.
So far 15 teams have entered, including a handful from Stanford University as well as from further afield at the genetics department at George Washington University in DC and the Albert Einstein College of Medicine, New York.
But they face even fiercer competition outside the prize. Google recently unveiled its own $1.2 billion research centre Calico, or the California Life Company, aiming to achieve the tech giant’s boldest ambition yet – extend the human lifespan.
While their work, which is led by Arthur Levinson, former CEO of biotech firm Genentech, is shrouded in secrecy, they are said to be focusing on developing drugs for age-related neurodegenerative disorders.
“Our goal is to make progress on a very basic challenge: how to help people stay healthier for longer,” Mr Levinson said of the project.
Meanwhile, Craig Venter, the geneticist who sequenced the first human genome, has set up his own company, Human Longevity Inc., alongside stem cell pioneer Robert Hariri.
They plan to sequence one million human genomes, including those of several supercentenarians, in order to build the world’s largest database of human genetic variation. By looking at the DNA, they hope to discover a common feature among those living longer.
Dr de Grey, a British gerontologist at the SENS Foundation in Silicon Valley, has dedicated his life’s work to solving the perennial problem of death. He believes it should be treated as a disease and can be postponed indefinitely.
“Since the dawn of civilisation, humanity has been enslaved by the knowledge that no lifestyle choice, no medicine, no quirk of fate, can enable anyone to live for more than a few decades without suffering a progressive decline that leads inevitably to death,” the Cambridge University researcher says.
“But scientists have already drawn a road map to defeat biological aging and will one day show there is no such inevitability. This is a when, not an if.”
However, he takes a different approach, looking at fixing the damage caused by metabolism.
The idea of reverse-engineering aging is not a new one. The American Academy of Anti-aging Medicine was set up in 1992, but only recently has the idea gained traction in mainstream medicine.
Dr Yun believes there had not been the support or funding needed to galvanise the field until now. “No one was incentivised to fix the underlying causes of aging as too many of the big players in the medical and insurance industries benefit from the current system,” he says.
There has also not been much of a public appetite, which scientists put down to lack of understanding. A recent survey by Pew Research found that most Americans did not actually want to live beyond the accepted human lifespan.
When asked if they wanted medical treatments that slowed the aging process and allowed the average person to live to at least 120 years, 56 per cent surveyed said no. When asked how long they wanted to live, the median answer was 90.
Even Bill Gates, Microsoft founder and philanthropist, seemed to write off the desire to extend life as Silicon Valley hubris. “It seems pretty egocentric while we still have malaria and TB for rich people to fund things so they can live longer,” he said, however continued “It would be nice to live longer though I admit.”
Along with the reasoning that it felt “fundamentally unnatural”, a number of survey respondents said they would worry about overpopulation and a potential lack of resources.
But Dr Yun says society will adapt to changes in life expectancy. “Just a few generations ago it was common to see people going into the workforce at 13, and dying before they turned 45. Things have changed since then – people now stay in education for longer, and have children and retire much later.
“Plus if people begin living longer, they will care more about what the world will look like in the future – impact concerns will shift from being their children’s problem to being their problem.”
Life-extending technology has become a booming industry in Silicon Valley.
Google X and Proteus Digital Health are among a dozen or so companies working on “ingestible tech” that they hope will go some way towards keeping us alive and healthy for longer.
Google’s pill, which is filled with tiny iron-oxide nanoparticles that enter the bloodstream, is able to identify cancer tumour cells, which give off early biochemical signals when they contract the disease.
Proteus, having already gained FDA approval, is now in talks with Britain’s National Health Service about the possible use of its sensor pill, which sends biological information it retrieves from the body to a smartphone.
At the same time, the XPrize Foundation, a charity that runs technology competitions, is working on developing a hand-held all-in-one diagnostic device. With one drop of blood, the “tricorder” will be able to accurately detect conditions such as diabetes and tuberculosis as well as measuring blood pressure and temperature – all from the comfort of your home.
Grant Campany, director of the XPrize, told The Sunday Telegraph: “It will all but eradicate the need to see a doctor for check-ups. The device will help people take their health back into their own hands.”
The Longevity Prize’s Dr Kim, who has spent the last 10 years looking into the causes of aging, believes we cannot afford not to come up with a solution. “We shouldn’t just be thinking of how to treat diseases like cancer, we should be looking at how to prevent them by figuring out why old people are much more likely to get them,” he says. “If you could take 80-year-olds and make them biologically more like 60-year-olds, that’s a 15-fold decrease in the rate of cancer right there.
“If we solve this, we all win.”
HONG KONG: Scientists mapping the genome for the world’s longest-lived mammal, the bowhead whale, have found the longevity genes that give it a 200-year-plus lifespan — and say the discoveries might be used to extend human life.
The genome mapping is a result of two separate studies carried out in the US and UK allowing scientists to identify a small number of genes linked to cancer resistance, DNA damage repair and increased longevity.
Joao Pedro de Magalhaes, the lead researcher of the UK-based study at Liverpool University, said the discovery could lead to those genes being used to help humans enjoy a longer life.
The work, conducted in the Liverpool Centre for Genomics Research was done in collaboration with scientists in Alaska, Denmark, Ireland, Spain and South Korea, and compared the bowhead’s genes with a minke whale, which typically lives for only 30-50 years.
Using this method, the researchers found that the bowhead had unique mutations in two genes linked to lifespan in animals.
These are the ERCC1 gene, which is believed to repair DNA, increase cancer resistance and slow ageing, and the PCNA gene, which is also linked to DNA repair.
Magalhaes is now seeking funding for a project that will insert the whales’ genes into mice to see if that improves their resistance to disease, ‘The Sunday Times’ reported.
If that is successful, the scientist hopes to test its effects on humans either by using drugs that activate the genes already inside the body or by incorporating the bowhead’s genes into human cells and inserting them back into people.
Magalhaes’ work follows a study published in October by Harvard Medical School researchers which also analysed the bowhead’s genes and made similar findings.
They proposed that similar genetic patterns also existed in other remarkably long-lived animals such as the naked mole rat and the Brandt’s bat.
In a research area that will generate blockbuster profits if/when it pans out, a science team reported creating new hair cells from pluripotent stem cells in a recent issue of PLOS (Proceedings of the Library of Science) One.
The team, led by the Sanford Burnham Medical Research Institute, got their results using two different kinds of cells: embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. ES cells can form all body cells. IPS cells can, as well. The difference is iPS cells are derived from adult cells, not in vitro fertilization (IVF) clinic embryos. The clock is turned back on the adult cells, until they reach a pluripotent state like that of ES cells.
“The relative simplicity of the procedure to derive [dermal-papilla]-like cells was a pleasant surprise,” Sanford Burnham developmental biologist Alexey Terskikh told Drug Discovery & Development. Terskikh is senior author on the paper. “To the best of my knowledge, we are the first team to report the generation of hair inducing cells” from embryonic stem cells. “The most critical next step is to investigate whether this approach works in humans.”
The new approach
Terskikh’s group believes their creation of neural crest cells from ES cells, which then formed dermal papilla cells, was a key step. Dermal papilla cells regulate hair-follicle formation and growth cycle. Limited adult dermal papilla (DP) cells do not work as hair transplants as they generally can’t be obtained in the large amounts, and can quickly lose hair-follicle forming ability in culture.
But neural crest cells transiently arise from the dorsal neural tube during development, and give rise to many tissues at that time, including hair follicle cells. So Terskikh’s group first worked on persuading their pluripotent cells to become neural crest cells. Human ES cells “have been directed to various cell fates including hair follicle epidermal cells—keratinocytes; however, the derivation of DP cells have not been reported” from ES cells, the team wrote. “Here we describe for the first time the derivation of functional DP-like cells human embryonic stem cells.”
Alexey Terskikh, Ph.D, the Sanford Burnham Medical Research Institute developmental biologist behind a recent effort to create hair cells from stem cells Alexey Terskikh, Ph.D, the Sanford Burnham Medical Research Institute developmental biologist behind a recent effort to create hair cells from stem cells The group reported their human ES-cell derived neural crest cells, cultured in serum, progressively acquired the markers of DP cells, and gave rise to cell populations with “robust” hair-inducing potential in mice. They speculated the superior hair-creation capacity of their pluripotent cell derived DPs to most reported adult DPs may have to do with the resemblance of their cells to embryonic or neonatal DP precursor cells.
The group also reported their cells are heterogeneous, a “mixed population” of neural-crest-derived cells that “contain DP-like cells with hair-inducing properties, but also might contain melanocyte- and keratinocyte-forming cells.” Therefore, “further analysis…is needed to address this question.”
The group also noted they had more success with human ES cells than with human IPS cells. They only achieved hair cells with one of three iPS cell lines. However, if many lines are used, hair cells should ultimately result, they wrote.
Overall, the group reported, “our results suggest that the intermediate step of hESC differentiation into the NC [neural crest] lineage seems critical, skipping the NC induction results in a complete loss of hair-inducing activity.” The group believes that directing human ES cells to neural crest cells “might limit the variety of mesenchymal cell types to the subset that is developmentally specified downstream from NC cells in skin (e.g. cephalic DP during development, melanocytes, cephalic bulge).” Resulting cultures become “enriched in hair-inducing DP-like cells using relatively common mesenchymal-enriching conditions, such as differentiation in serum containing medium and selection for the adherent cell types.”
The group said adult skin-derived precursors have been found in the past to be “highly potent in hair induction, but progressive loss” of those cells during aging “might hamper the process of isolation” of those cells.
In 2013, a Columbia University and Durham University team reported pairing up to generatesignificant hair growth, for the first time, from adult DP cells using unique 3-D cultures. Results varied between donor cells, but those groups reported they were perfecting that approach.
It’s been known for decades that some metals, including iron, accumulate in human tissues during aging and that toxic levels of iron have been linked to neurologic diseases. Common belief has held that iron accumulation happens as a result of the aging process. But research in the nematode C. elegans in the Lithgow lab at the Buck Institute shows that iron accumulation itself may also be a significant contributor to the aging process, causing dysfunction and malfolding of proteins already implicated in the aging process. The research is online in Aging
Similar to what happens in humans and other mammals, researchers found that levels of calcium, copper, iron and manganese increased as the worms aged. But iron accumulated much more than the others, said Buck faculty Gordon Lithgow, PhD, senior scientist on the project. “We were drawn to iron because there is all this literature that links excess iron to Alzheimer’s and Parkinson’s.”
Researchers began manipulating the nematode’s diet. “We fed iron to four day-old worms, and within a couple of days they looked like 15 day-old worms,” said Lithgow. “Excess iron accelerated the aging process.” Lithgow says excess iron is known to generate oxidative stress and researchers expected to see changes in the worm based on that toxicity. “Instead, what we saw looked much more like normal aging,” said Lithgow. “The iron was causing dysfunction and aggregation in proteins that have already been associated with the aging process. Now we’re wondering if excess iron also drives aging. ”
Researchers, led by graduate student Ida Klang, also treated normal nematodes with the FDA-approved metal chelator CaEDTA – a drug that’s used in humans at risk for lead poisoning. The drug slowed age-related accumulation of iron and extended the healthspan and lifespan of the nematodes. Klang also gave the drug to worms genetically bred to develop specific protein aggregations implicated in human disease. The chelator was also protective in those animals.
Lithgow says the work has implications for the aging research field. “Maintaining the proper balance of metals is key to good health throughout the lifespan, and it’s pretty obvious that this delicate balance can go off-kilter with age,” he said. “This is a phenomena that has not been extensively studied by aging researchers and it’s an area that has potential for positive exploitation.” As far as the general public is concerned, Lithgow was quick to warn people away from taking CaEDTA and other available metal chelators as anti-aging medication. “CaEDTA has a very blunt mechanism of action and is associated with dangerous side effects in humans and the track record for other chelators is not well established,” said Lithgow, who urged people to talk to their physicians about the use of iron supplementation, especially for postmenopausal women.
Lithgow said his lab wants to find new chelators that act more like drugs and then move those drugs into testing in mice.
Just three years ago, a patient at Sahlgrenska University Hospital received a blood vessel transplant grown from her own stem cells.
Professors Sumitran-Holgersson and Olausson have published a new study in EBioMedicine based on two other transplants that were performed in 2012 at Sahlgrenska University Hospital. The patients, two young children, had the same condition as in the first case they were missing the vein that goes from the gastrointestinal tract to the liver.
“Once again we used the stem cells of the patients to grow a new blood vessel that would permit the two organs to collaborate properly,” Professor Olausson says.
This time, however, Professor Sumitran-Holgersson, found a way to extract stem cells that did not necessitate taking them from the bone marrow.
“Drilling in the bone marrow is very painful,” she says. “It occurred to me that there must be a way to obtain the cells from the blood instead.”
The fact that the patients were so young fueled her passion to look for a new approach. The method involved taking 25 milliliter (approximately 2 tablespoons) of blood, the minimum quantity needed to obtain enough stem cells.
Professor Sumitran-Holgersson’s idea turned out to surpass her wildest expectations — the extraction procedure worked perfectly the very first time.
“Not only that, but the blood itself accelerated growth of the new vein,” Professor Sumitran-Holgersson says. “The entire process took only a week, as opposed to a month in the first case. The blood contains substances that naturally promote growth.”
Professors Olausson and Sumitran-Holgersson have treated three patients so far. Two of the three patients are still doing well and have veins that are functioning as they should. In the third case the child is under medical surveillance and the outcome is more uncertain.
They researchers have now reached the point that they can avoid taking painful blood marrow samples and complete the entire process in the matter of a week.
“We believe that this technological progress can lead to dissemination of the method for the benefit of additional groups of patients, such as those with varicose veins or myocardial infarction, who need new blood vessels,” Professor Holgersson says. “Our dream is to be able to grow complete organs as a way of overcoming the current shortage from donors.”
1.Michael Olausson, Vijay Kumar Kuna, Galyna Travnikova, Henrik Bäckdahl, Pradeep B. Patil, Robert Saalman, Helena Borg, Anders Jeppsson, Suchitra Sumitran-Holgersson. In vivo application of tissue-engineered veins using autologous peripheral whole blood: A proof of concept study. EBioMedicine, 2014; DOI: 10.1016/j.ebiom.2014.09.001
A new procedure can quickly and efficiently increase the length of human telomeres, the protective caps on the ends of chromosomes that are linked to aging and disease, according to scientists at the Stanford University School of Medicine. It causes a significant increase in telomere length soon after the procedure, but does not continue to increase length unless it is done again at a later date. This is a major advantage since it give researchers and potentially later on medical doctors the ability to control the degree of telomere lengthening.
Treated cells behave as if they are much younger than untreated cells, multiplying with abandon in the laboratory dish rather than stagnating or dying.
The procedure, which involves the use of a modified type of RNA, will improve the ability of researchers to generate large numbers of cells for study or drug development, the scientists say. Skin cells with telomeres lengthened by the procedure were able to divide up to 40 more times than untreated cells. The research may point to new ways to treat diseases and aging caused by shortened telomeres.
Telomeres are the protective caps on the ends of the strands of DNA called chromosomes, which house our genomes. In young humans, telomeres are about 8,000-10,000 nucleotides long. They shorten with each cell division, however, and when they reach a critical length the cell stops dividing or dies. This internal “clock” makes it difficult to keep most cells growing in a laboratory for more than a few cell doublings.
‘Turning back the internal clock’
“Now we have found a way to lengthen human telomeres by as much as 1,000 nucleotides, turning back the internal clock in these cells by the equivalent of many years of human life,” said Helen Blau, PhD, professor of microbiology and immunology at Stanford and director of the university’s Baxter Laboratory for Stem Cell Biology. “This greatly increases the number of cells available for studies such as drug testing or disease modeling.”
A paper describing the research was published today in the FASEB Journal. Blau, who also holds the Donald E. and Delia B. Baxter Professorship, is the senior author. Postdoctoral scholar John Ramunas, PhD, of Stanford shares lead authorship with Eduard Yakubov, PhD, of the Houston Methodist Research Institute.
The researchers used modified messenger RNA to extend the telomeres. RNA carries instructions from genes in the DNA to the cell’s protein-making factories. The RNA used in this experiment contained the coding sequence for TERT, the active component of a naturally occurring enzyme called telomerase. Telomerase is expressed by stem cells, including those that give rise to sperm and egg cells, to ensure that the telomeres of these cells stay in tip-top shape for the next generation. Most other types of cells, however, express very low levels of telomerase.
Transient effect an advantage
The newly developed technique has an important advantage over other potential methods: It’s temporary. The modified RNA is designed to reduce the cell’s immune response to the treatment and allow the TERT-encoding message to stick around a bit longer than an unmodified message would. But it dissipates and is gone within about 48 hours. After that time, the newly lengthened telomeres begin to progressively shorten again with each cell division.
The transient effect is somewhat like tapping the gas pedal in one of a fleet of cars coasting slowly to a stop. The car with the extra surge of energy will go farther than its peers, but it will still come to an eventual halt when its forward momentum is spent. On a biological level, this means the treated cells don’t go on to divide indefinitely, which would make them too dangerous to use as a potential therapy in humans because of the risk of cancer.
The researchers found that as few as three applications of the modified RNA over a period of a few days could significantly increase the length of the telomeres in cultured human muscle and skin cells. A 1,000-nucleotide addition represents a more than 10 percent increase in the length of the telomeres. These cells divided many more times in the culture dish than did untreated cells: about 28 more times for the skin cells, and about three more times for the muscle cells.
“We were surprised and pleased that modified TERT mRNA worked, because TERT is highly regulated and must bind to another component of telomerase,” said Ramunas. “Previous attempts to deliver mRNA-encoding TERT caused an immune response against telomerase, which could be deleterious. In contrast, our technique is nonimmunogenic. Existing transient methods of extending telomeres act slowly, whereas our method acts over just a few days to reverse telomere shortening that occurs over more than a decade of normal aging. This suggests that a treatment using our method could be brief and infrequent.”
Potential uses for therapy
“This new approach paves the way toward preventing or treating diseases of aging,” said Blau. “There are also highly debilitating genetic diseases associated with telomere shortening that could benefit from such a potential treatment.”
Blau and her colleagues became interested in telomeres when previous work in her lab showed that the muscle stem cells of boys with Duchenne muscular dystrophy had telomeres that were much shorter than those of boys without the disease. This finding not only has implications for understanding how the cells function — or don’t function — in making new muscle, but it also helps explain the limited ability to grow affected cells in the laboratory for study.
The researchers are now testing their new technique in other types of cells.
“This study is a first step toward the development of telomere extension to improve cell therapies and to possibly treat disorders of accelerated aging in humans,” said John Cooke, MD, PhD. Cooke, a co-author of the study, formerly was a professor of cardiovascular medicine at Stanford. He is now chair of cardiovascular sciences at the Houston Methodist Research Institute.
“We’re working to understand more about the differences among cell types, and how we can overcome those differences to allow this approach to be more universally useful,” said Blau, who also is a member of the Stanford Institute for Stem Cell Biology and Regenerative Medicine.
Recent studies have shown that added sugars, particularly those containing fructose, are a principal driver of diabetes and pre-diabetes, even more so than other carbohydrates. Clinical experts writing in Mayo Clinic Proceedings challenge current dietary guidelines that allow up to 25% of total daily calories as added sugars, and propose drastic reductions in the amount of added sugar, and especially added fructose, people consume.
Worldwide, approximately one in ten adults has type 2 diabetes, with the number of individuals afflicted by the disease across the globe more than doubling from 153 million in 1980 to 347 million in 2008. In the United States, 29 million adults (one in eleven) have type 2 diabetes and another 86 million (more than one in three) have pre-diabetes.
“At current levels, added-sugar consumption, and added-fructose consumption in particular, are fueling a worsening epidemic of type 2 diabetes,” said lead author James J. DiNicolantonio, PharmD, a cardiovascular research scientist at Saint Luke’s Mid America Heart Institute, Kansas City, MO. “Approximately 40% of U.S. adults already have some degree of insulin resistance with projections that nearly the same percentage will eventually develop frank diabetes.”
The net result of excess consumption of added fructose is derangement of both overall metabolism and global insulin resistance say the authors. Other dietary sugars not containing fructose seem to be less detrimental in these respects. Indeed, several clinical trials have shown that compared to glucose or starch, isocaloric exchange with fructose or sucrose leads to increases in fasting insulin, fasting glucose, and the insulin/glucose responses to a sucrose load. “This suggests that sucrose (in particular the fructose component) is more harmful compared to other carbohydrates,” added Dr. DiNicolantonio. Dr. DiNicolantonio and his co-authors, James H O’Keefe, MD, Saint Luke’s Mid America Heart Institute, Kansas City, MO, and Sean C. Lucan, MD, MPH, MS, a family physician at Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, examined animal experiments and human studies to come to their conclusions.
Data from recent trials suggest that replacing glucose-only starch with fructose-containing table sugar (sucrose) results in significant adverse metabolic effects. Adverse effects are broader with increasing baseline insulin resistance and more profound with greater proportions of added fructose in the diet.
The totality of the evidence is compelling to suggest that added sugar, and especially added fructose (usually in the form of high-fructose corn syrup and table sugar), are a serious and growing public health problem, according to the authors.
The 2010 Dietary Guidelines for Americans say it is acceptable for some people to consume up to 19% of calories from added sugars, and the Institute of Medicine permits up to 25% of total calories from added sugars. In contrast, the World Health Organization recommends that added sugars should make up no more than 10% of an entire day’s caloric intake, with a proposal to lower this level to 5% or less for optimal health. Such levels would be more in line with what the authors would recommend and similarly restrictive to existing American Heart Association (AHA) recommendations–to consume no more than six teaspoons (24 grams) of sugar per day for women and no more than nine teaspoons (36 grams) of sugar per day for men.
While fructose is found naturally in some whole foods like fruits and vegetables, consuming these foods poses no problem for human health. Indeed, consuming fruits and vegetables is likely protective against diabetes and broader cardiometabolic dysfunction, explained DiNicolantonio and colleagues. The authors propose that dietary guidelines should be modified to encourage individuals to replace processed foods, laden with added sugars and fructose, with whole foods like fruits and vegetables. “Most existing guidelines fall short of this mark at the potential cost of worsening rates of diabetes and related cardiovascular and other consequences,” they wrote.
The authors also think there should be incentives for industry to add less sugars, especially fructose-containing varieties, to food-and-beverage products. And they conclude that at “an individual level, limiting consumption of foods and beverages that contain added sugars, particularly added fructose, may be one of the single most effective strategies for ensuring one’s robust future health.”