For the first time, researchers reveal a causal link between RNA splicing and aging.
The finding sheds light on the biological role of splicing in lifespan and suggests that manipulating specific splicing factors in humans might help promote healthy aging.
“What kills neurons in Alzheimer’s is certainly different from what causes cardiovascular disease, but the shared underlying risk factor for these illnesses is really age itself,” said William Mair, assistant professor of genetics and complex diseases at Harvard Chan School and the study’s senior author.
While a considerable amount is known about how dysfunction at the two ends of this process – genes and proteins – can accelerate aging, strikingly little is known about how the middle part, which includes RNA splicing, influences aging.
“Although we know that specific splicing defects can lead to disease, we were really intrigued about de-regulation of RNA splicing as a driver of the aging process itself, because practically nothing is known about that,” said Mair.
Notably, the worms’ cells are transparent, so Heintz and her colleagues harnessed fluorescent genetic tools to visualize the splicing of a single gene in real-time throughout the aging process.
Not only did the scientists observe variability on a population level – after five days, some worms showed a youthful pattern of splicing while others exhibited one indicative of premature aging – but they could also use these differences in splicing to predict individual worms’ lifespans prior to any overt signs of old age.
The finding suggests that splicing could play a broad role in the aging process, both in worms as well as humans.
As they dug more deeply into the molecular links between splicing and aging, Heintz and her colleagues zeroed in on one particular component of the splicing apparatus in worms, called splicing factor 1 – a factor also present in humans.
“These are fascinating results, and suggest that variability in RNA splicing might be one of the smoking guns of the aging process,” said Mair.
A new study from UC Berkeley found that tissue health and repair dramatically decline in young mice when half of their blood is replaced with blood from old mice.
“Our study suggests that young blood by itself will not work as effective medicine,” said Irina Conboy, associate professor in the Department of Bioengineering at UC Berkeley. “It’s more accurate to say that there are inhibitors in old blood that we need to target to reverse aging.”
The study was published today in the journal Nature Communications. The research was supported by funding from the National Institutes of Health, SENS Research Foundation, Rogers’ Family and Calico.
In 2005, Conboy and colleagues published a study in Nature that found evidence for tissue rejuvenation in older mice when they are surgically joined to younger mice so that blood is exchanged between the two. Despite remaining questions about the mechanism underlying this rejuvenation, media coverage of the study fixated on the potential of young blood to reverse the aging process, and on comparisons to vampires, which was not the takeaway from the study, Conboy said. In the years since the 2005 study, scientists have spent millions to investigate the potential medical properties of youthful blood with enterprises emerging to infuse old people with young blood.
“What we showed in 2005 was evidence that aging is reversible and is not set in stone,” Conboy said. “Under no circumstances were we saying that infusions of young blood into elderly is medicine.”
Blood exchange in humans is FDA-approved for a few devastating illnesses (auto-immunity, for example, where self-reacting antibodies are removed), but high volume or repeated additions of blood or its components to genetically different people is known to have side effects of immune rejection, leading to organ failure.
While the experimental model used in the 2005 study found evidence that some aspects of aging may be reversed, the techniques used in the study do not allow scientists to precisely control the exchange of blood, which is necessary to dig deeper into blood’s effect on aging.
When two mice are sutured together, a technique called parabiosis, blood is not the only thing that is exchanged in this setup; organs are also shared, so old mice get access to younger lungs, thymus-immune system, heart, liver and kidneys. In surgical suturing it takes weeks to a month for the effects of blood to take place and the precise timing is not actually known. Nor is the precise amount of the exchanged blood.
In the new study, Conboy and colleagues developed an experimental technique to exchange blood between mice without joining them so that scientists can control blood circulation and conduct precise measurements on how old mice respond to young blood, and vice versa. In the new system, mice are connected and disconnected at will, removing the influence of shared organs or of any adaptation to being joined. One of the more surprising discoveries of this study was the very quick onset of the effects of blood on the health and repair of multiple tissues, including muscle, liver and brain. The effects were seen around 24 hours after exchange.
With the new experimental setup, the research team repeated the experiments from 2005. In each test, blood was exchanged between an old mouse and a young mouse until each mouse had half its blood from the other. The researchers then tested various indicators of aging in each mouse, such as liver cell growth as well as liver fibrosis and adiposity (fat), brain cell development in the region that is needed for learning and memory, muscle strength and muscle tissue repair. In many of these experiments, older mice that received younger blood saw either slight or no significant improvements compared to old mice with old blood. Young mice that received older blood, however, saw large declines in most of these tissues or organs.
The most telling data was found when researchers tested blood’s impact on new neuron production in the area of the brain where memory and learning are formed. In these experiments, older mice showed no significant improvement in brain neuron stem cells after receiving younger blood, but younger mice that received older blood saw a more than twofold drop in brain cell development compared to normal young mice. The researchers think that many benefits seen in old mice after receiving young blood might be due to the young blood diluting the concentration of inhibitors in the old blood.
“Under no circumstances did young blood improve brain neurogenesis in our experiments,” Conboy said. “Old blood appears to have inhibitors of brain cell health and growth, which we need to identify and remove if we want to improve memory.”
The research team has begun to investigate specific molecules in old blood that might cause inhibition of cell development, but future experiments are needed for a clear picture of why young animals are worse off with old blood.
A team of University of Pittsburgh researchers has uncovered new details about the biology of telomeres, “caps” of DNA that protect the tips of chromosomes and play key roles in a number of health conditions, including cancer, inflammation and aging.
The new findings were published today in the journal Nature Structural and Molecular Biology.
Telomeres, composed of repeated sequences of DNA, are shortened every time a cell divides and therefore become smaller as a person ages. When they become too short, telomeres send a signal to the cell to stop dividing permanently, which impairs the ability of tissues to regenerate and contributes to many aging-related diseases, explained lead study author Patricia Opresko, Ph.D., associate professor of Environmental and Occupational Health at Pitt, and member of the University of Pittsburgh Cancer Institute Molecular and Cellular Cancer Biology program and Carnegie Mellon University Center for Nucleic Acids Science and Technology.
In contrast, in most cancer cells, levels of the enzyme telomerase, which lengthens telomeres, are elevated, allowing them to divide indefinitely.
“The new information will be useful in designing new therapies to preserve telomeres in healthy cells and ultimately help combat the effects of inflammation and aging. On the flip side, we hope to develop mechanisms to selectively deplete telomeres in cancer cells to stop them from dividing,” said Dr. Opresko.
A number of studies have shown that oxidative stress—a condition where damaging molecules known as free radicals build up inside cell—accelerates telomere shortening. Free radicals can damage not only the DNA that make up telomeres, but also the DNA building blocks used to extend them.
Oxidative stress is known to play a role in many health conditions, including inflammation and cancer. Damage from free radicals, which can be generated by inflammation in the body as well as environmental factors, is thought to build up throughout the aging process.
The goal of the new study was to determine what happens to telomeres when they are damaged by oxidative stress. The researchers suspected that oxidative damage would render telomerase unable to do its job.
“Much to our surprise, telomerase could lengthen telomeres with oxidative damage,” Dr. Opresko said. “In fact, the damage seems to promote telomere lengthening.”
Next, the team looked to see what would happen if the building blocks used to make up telomeres were instead subjected to oxidative damage. They found that telomerase was able to add a damaged DNA precursor molecule to the end of the telomere, but was then unable to add additional DNA molecules.
The new results suggest that the mechanism by which oxidative stress accelerates telomere shortening is by damaging the DNA precursor molecules, not the telomere itself. “We also found that oxidation of the DNA building blocks is a new way to inhibit telomerase activity, which is important because it could potentially be used to treat cancer.”
Dr. Opresko and her team are now beginning to further explore the consequences of oxidative stress on telomeres, using a novel photosensitizer, developed by Marcel Bruchez at Carnegie Mellon University that produces oxidative damage selectively in telomeres. “Using this exciting new technology, we’ll be able to learn a lot about what happens to telomeres when they are damaged, and how that damage is processed,” she said.
Safety of NMN being tested in small clinical trial in Japan
Much of human health hinges on how well the body manufactures and uses energy. For reasons that remain unclear, cells’ ability to produce energy declines with age, prompting scientists to suspect that the steady loss of efficiency in the body’s energy supply chain is a key driver of the aging process.
Now, scientists at Washington University School of Medicine in St. Louis have shown that supplementing healthy mice with a natural compound called NMN can compensate for this loss of energy production, reducing typical signs of aging such as gradual weight gain, loss of insulin sensitivity and declines in physical activity.
The study is published Oct. 27 in the journal Cell Metabolism.
“We have shown a way to slow the physiologic decline that we see in aging mice,” said Shin-ichiro Imai, MD, PhD, a professor of developmental biology and of medicine. “This means older mice have metabolism and energy levels resembling that of younger mice. Since human cells rely on this same energy production process, we are hopeful this will translate into a method to help people remain healthier as they age.”
Imai is working with researchers conducting a clinical trial to test the safety of NMN in healthy people. The phase 1 trial began earlier this year at Keio University School of Medicine in Tokyo.
With age, the body loses its capacity to make a key element of energy production called NAD (nicotinamide adenine dinucleotide). Past work by Imai and co-senior author Jun Yoshino, MD, PhD, an assistant professor of medicine, has shown that NAD levels decrease in multiple tissues as mice age. Past research also has shown that NAD is not effective when given directly to mice so the researchers sought an indirect method to boost its levels. To do so, they only had to look one step earlier in the NAD supply chain to a compound called NMN (nicotinamide mononucleotide).
NMN can be given safely to mice and is found naturally in a number of foods, including broccoli, cabbage, cucumber, edamame and avocado. The new study shows that when NMN is dissolved in drinking water and given to mice, it appears in the bloodstream in less than three minutes. Importantly, the researchers also found that NMN in the blood is quickly converted to NAD in multiple tissues.
“We wanted to make sure that when we give NMN through drinking water, it actually goes into the blood circulation and into tissues,” Imai said. “Our data show that NMN absorption happens very rapidly.”
To determine the long-term effects of giving NMN, Imai, Yoshino and their colleagues studied three groups of healthy male mice fed regular mouse chow diets. Starting at five months of age, one group received a high dose of NMN-supplemented drinking water, another group received a low dose of the NMN drinking water, and a third group served as a control, receiving no NMN. The researchers compared multiple aspects of physiology between the groups, first at 5 months of age and then every three months, until the mice reached 17 months of age. Typical laboratory mice live about two years.
The researchers found a variety of beneficial effects of NMN supplementation, including in skeletal muscle, liver function, bone density, eye function, insulin sensitivity, immune function, body weight and physical activity levels. But these benefits were seen exclusively in older mice.
“When we give NMN to the young mice, they do not become healthier young mice,” Yoshino said. “NMN supplementation has no effect in the young mice because they are still making plenty of their own NMN. We suspect that the increase in inflammation that happens with aging reduces the body’s ability to make NMN and, by extension, NAD.”
In skeletal muscle, the investigators — including the study’s first author, Kathryn Mills, the research supervisor in Imai’s lab — found that NMN administration helps energy metabolism by improving the function of mitochondria, which operate as cellular power plants. They also found that mice given NMN gained less weight with aging even as they consumed more food, likely because their boosted metabolism generated more energy for physical activity. The researchers also found better function of the mouse retina with NMN supplementation, as well as increased tear production, which is often lost with aging. They also found improved insulin sensitivity in the older mice receiving NMN, and this difference remained significant even when they corrected for differences in body weight.
In a paper published earlier this year in Cell Reports, Yoshino and his colleagues revealed more details of how NAD works in influencing glucose metabolism and the body’s fat tissue. In that study, the mice had a defect in the ability to manufacture NAD only in the body’s fat tissue. The rest of their tissues and organs were normal.
“Even though NAD synthesis was stopped only in the fat tissue, we saw metabolic dysfunction throughout the body, including the skeletal muscle, the heart muscle, the liver and in measures of the blood lipids,” Yoshino said. “When we gave NMN to these mice, these dysfunctions were reversed. That means NAD in adipose tissue is a critical regulator of whole body metabolism.”
Added Imai, “This is important because Jun showed that if you mess up NAD synthesis only in fat tissue, you see insulin resistance everywhere. Adipose tissue must be doing something remarkable to control whole body insulin sensitivity.”
During the long-term NMN study in healthy mice, Imai also said they monitored the animals for any potential increase in cancer development as a result of NMN administration.
“Some tumor cells are known to have a higher capability to synthesize NAD, so we were concerned that giving NMN might increase cancer incidence,” Imai said. “But we have not seen any differences in cancer rates between the groups.”
The phase 1 trial in Japan is using NMN manufactured by Oriental Yeast Co., which also provided the NMN used in these mouse studies. Outside of this clinical trial, high-grade NMN for human consumption is not commercially available. But there’s always broccoli.
Ever since last summer, when Lynn Gemmell’s dog, Bela, was inducted into the trial of a drug that has been shown to significantly lengthen the lives of laboratory mice, she has been the object of intense scrutiny among dog park regulars.
To those who insist that Bela, 8, has turned back into a puppy — “Look how fast she’s getting that ball!” — Ms. Gemmell has tried to turn a deaf ear. Bela, a Border collie-Australian shepherd mix, may have been given a placebo, for one thing.
The drug, rapamycin, which improved heart health and appeared to delay the onset of some diseases in older mice, may not work the same magic in dogs, for another. There is also a chance it could do more harm than good. “This is just to look for side effects, in dogs,” Ms. Gemmell told Bela’s many well-wishers.
Technically that is true. But the trial also represents a new frontier in testing a proposition for improving human health: Rather than only seeking treatments for the individual maladies that come with age, we might do better to target the biology that underlies aging itself.
While the diseases that now kill most people in developed nations — heart disease, stroke, Alzheimer’s, diabetes, cancer — have different immediate causes, age is the major risk factor for all of them. That means that even treatment breakthroughs in these areas, no matter how vital to individuals, would yield on average four or five more years of life, epidemiologists say, and some of them likely shadowed by illness.
A drug that slows aging, the logic goes, might instead serve to delay the onset of several major diseases at once. A handful of drugs tested by federally funded laboratories in recent years appear to extend the healthy lives of mice, with rapamycin and its derivatives, approved by the Food and Drug Administration for organ transplant patients and to treat some types of cancer, so far proving the most effective. In a 2014 study by the drug company Novartis, the drug appeared to bolster the immune system in older patients. And the early results in aging dogs suggest that rapamycin is helping them, too, said Matt Kaeberlein, a biology of aging researcher at the University of Washington who is running the study with a colleague, Daniel Promislow.
But scientists who champion the study of aging’s basic biology — they call it “geroscience” — say their field has received short shrift from the biomedical establishment. And it was not lost on the University of Washington researchers that exposing dog lovers to the idea that aging could be delayed might generate popular support in addition to new data.
“Many of us in the biology of aging field feel like it is underfunded relative to the potential impact on human health this could have,” said Dr. Kaeberlein, who helped pay for the study with funds he received from the university for turning down a competing job offer. “If the average pet owner sees there’s a way to significantly delay aging in their pet, maybe it will begin to impact policy decisions.”
Researchers may have found a way to slow down or prevent memory problems that arise in old age and which can become devastating in patients with dementia.
The fresh hope comes from a series of studies in humans and mice that identified a protein which causes memory impairment when it builds up in the blood and brain with age. Scientists found that injections of the protein made young animals’ memories worse and reduced the growth of new neurons in their brains. Further studies showed that blocking the protein prevented memory loss in older animals, making them smarter than untreated animals of the same age.
Scientists found that injections of the protein made young animals’ memories worse and reduced the growth of new neurons in their brains. Further studies showed that blocking the protein prevented memory loss in older animals, making them smarter than untreated animals of the same age.
The findings are the latest to come from researchers in the US who have shown in previous work that blood plasma taken from young animals can rejuvenate the muscles, brains and other tissues of older animals.
Those studies have led scientists to suspect that blood plasma contains a cocktail of factors that either drive or counteract the natural ageing process. Major efforts are now underway to identify the different components at work in the hope of turning them into a therapy. A human trial to test the effects of young plasma on Alzheimer’s patients is already underway.