As medicine has improved, we are increasing our ability to treat disease and improve longevity. The deterioration of the body with age, though, is a whole other matter.

Scientists suggest that all we might need is some “house-keeping” of the brain, according to research just published in an early edition of the journal PNAS by a Portuguese team from the Centre for Neuroscience and Cell Biology (CNC) of the University of Coimbra.

The researchers might have also solved a 70-year old mystery: How can calorie restriction (a diet with low calories without malnutrition) delay ageing and increase longevity in animals from dogs to mice?

In their new study, Claudia Cavadas and her group have discovered that the key to this diet appears to be its ability to increase autophagy – the mechanism that recycles unwanted molecules in the cells, thereby avoiding malfunction in the hypothalamus, which has just been identified as the “control centre” for ageing. They also have identified the molecule that controls the process. It’s called neuropeptide Y (NPY), and its discovery raises the possibility that NPY could be used to develop techniques to control aging instead of just treating its consequences, like we do now.

The discovery may be a key to stopping the development of age-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s, a huge step forward, considering that science has thus far been incapable of treating, stopping or even fully understanding them. And in a rapidly aging world, a better control of these kinds of problems can prove crucial for everyone’s survival.

In fact, according to the UN, in less than a decade, 1 billion people will be older than 60. In Japan, more than 30% of the population is older than 60 years old, and in Europe, 16% of the population is over 65. So it is clear that our increasingly aging population needs to be kept as healthy and active as possible, or it will be financially and socially impossible for the world to cope. It is no surprise, then, that research to understand and control the deteriorating effects of aging is now a priority.

One thing that has been clear for a while now is that autophagy (or better, a reduction of it) is at the centre of the aging process. Low levels of autophagy?that is, impaired cellular “house-keeping”? is linked to ageing and age-related neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and Huntington’s diseases. This is easily explained as autophagy clears the cellular “debris” keeping neurons in good working order. The importance of the process in the brain is no surprise, since neurons have a lower ability to replenish themselves once they die or malfunction.

But about a year ago, there was a remarkable discovery that changed the field: The hypothalamus, which is a brain area that regulates energy and metabolism, was identified as the control centre for whole-body aging.

To Cavadas and her group, who have worked on aging and neuroscience for a long time, this was particularly exciting. They knew calorie restriction delayed aging and increased longevity and increased autophagy in the hypothalamus; but they also knew that it did the same to NPY and that mice without NPY did not respond to calorie restriction. Furthermore NPY, like autophagy, diminishes with age. All this, together with the discovery of the new role of the hypothalamus, suggested that this brain area and NPY were the key to the rejuvenating effects of calorie restriction.

So now all that was left was to connect the dots, and for that, the researchers started by taking neurons from the hypothalami of mice and growing them in a medium that mimicked a low caloric diet. They then measured rates of autophagy. As expected, autophagy levels in this calorie-restriction-like medium were much higher than normal, unless NPY was blocked, in which case the medium had no consequences on the neurons. So calorie restriction effect on the hypothalamic autophagy appeared to depend on NPY. To confirm this, the researchers then tested mice genetically modified to produce higher than normal quantities of NYP in their hypothalami. As expected, this led to higher levels of autophagy.

So calorie restriction seems to work by increasing the levels of NPY in the hypothalamus, which in turn triggers an increase in autophagy in its neurons, “rejuvenating” them and delaying aging symptoms. Cavadas and colleagues also identified the biochemical pathways involved in the NPY effect. This, however, is not the whole story, as it still does not explain why in some species, such as wild mice, calorie restriction has no effect.

But by adding a new piece to the puzzle of aging, the group’s research is an important step toward delaying the the body’s deterioration, allowing individuals to have healthier lives until the end, particularly with regard to the brain. Age-related neurodegenerative diseases seem to be unstoppable at the moment, and are not only an economic but also a huge social burden as patients became totally dependent on their families or the state.

In fact, in the US, more than 5 million people already suffer from Alzheimer’s (1 million have Parkinson’s), while in the UK this number is reaching 1 million. Just in the care of dementia patients, the UK health system is spending more than ?26 billion yearly (the equivalent to 38 billion dollars or 36 billion Euros). Age-related neurodegenerative diseases are already the fourth highest disease burden in the western world, and growing.

It will be interesting to further understand the long-debated mystery of the mechanism behind calorie restriction, and test to see if it works on humans as some believe (it does not work, for example, on wild mice). In fact, during World War II in Europe, when food was short, there was a sharp decrease in heart diseases (which are age-related) that rapidly rose once the war ended. The same reduction is observed in Okinawa island in Japan, where people eat on average less 30% of calories than the rest of the country. Whether a coincidence or not, it should be interesting to know what that that means in our “junk-food” society.

Using sugar, silicone, and a 3D printer, bioengineers at Rice University and surgeons at the University of Pennsylvania have created an implant with an intricate network of blood vessels that points toward a future of growing replacement tissues and organs for transplantation.

The research may provide a method to overcome one of the biggest challenges in regenerative medicine, i.e., how to deliver oxygen and nutrients to all cells in an artificial organ or tissue implant that takes days or weeks to grow in the lab prior to surgery.

The new study was performed by a research team led by Jordan Miller, Ph.D., assistant professor of bioengineering at Rice, and Pavan Atluri, M.D., assistant professor of surgery at Penn. The study showed that blood flowed normally through test constructs that were surgically connected to native blood vessels. The study (?In vivo anastomosis and perfusion of a 3D printed construct containing microchannel networks?) was published in Tissue Engineering Part C: Methods.

Dr. Miller said one of the hurdles of engineering large artificial tissues, such as livers or kidneys, is keeping the cells inside them alive. Tissue engineers have typically relied on the body’s own ability to grow blood vessels, for example, by implanting engineered tissue scaffolds inside the body and waiting for blood vessels from nearby tissues to spread to the engineered constructs. Dr. Miller noted that that process can take weeks, and cells deep inside the constructs often starve or die from lack of oxygen before they’re reached by the slow-approaching blood vessels.

“We had a theory that maybe we shouldn’t be waiting,” he explained. “We wondered if there were a way to implant a 3D printed construct where we could connect host arteries directly to the construct and get perfusion immediately. In this study, we are taking the first step toward applying an analogy from transplant surgery to 3D printed constructs we make in the lab.”

Dr. Miller and his team thought long-term about what the needs would be for transplantation of large tissues made in the laboratory. “What a surgeon needs in order to do transplant surgery isn’t just a mass of cells; the surgeon needs a vessel inlet and an outlet that can be directly connected to arteries and veins,” he added.

The research team worked together to develop a proof-of-concept construct, a small silicone gel about the size of a small candy gummy bear, using 3D printing. But rather than printing a whole construct directly, the scientists fabricated sacrificial templates for the vessels that would be inside the construct.

It’s a technique pioneered by Dr. Miller in 2012 and inspired by the intricate sugar glass cages crafted by pastry chefs to garnish desserts.

Using an open-source 3D printer that lays down individual filaments of sugar glass one layer at a time, the researchers printed a lattice of would-be blood vessels. Once the sugar hardened, the investigators placed it in a mold and poured in silicone gel. After the gel cured, Dr. Miller’s team dissolved the sugar, leaving behind a network of small channels in the silicone.

“They don’t yet look like the blood vessels found in organs, but they have some of the key features relevant for a transplant surgeon,” said Dr. Miller. “We created a construct that has one inlet and one outlet, which are about 1 millimeter in diameter, and these main vessels branch into multiple smaller vessels, which are about 600 to 800 microns.”

Collaborating surgeons at Penn in Dr. Atluri’s group connected the inlet and outlet of the engineered gel to a major artery in a small animal model. Using Doppler imaging technology, the team observed and measured blood flow through the construct and found that it withstood physiologic pressures and remained open and unobstructed for up to three hours.

“This study provides a first step toward developing a transplant model for tissue engineering where the surgeon can directly connect arteries to an engineered tissue,” said Dr. Miller. “In the future we aim to utilize a biodegradable material that also contains live cells next to these perfusable vessels for direct transplantation and monitoring long term.”

Back in the 1950s in a weird, vampiric experiment, scientists first showed that connecting the circulatory systems of old and young mice seems to rejuvenate the more elderly animals. A handful of labs have recently been racing to find factors in young blood that may explain this effect. Now, a Harvard University group that claims to have found one such antiaging protein has published a study countering critics who dismissed the work on the molecule as flawed.

Harvard stem cell biologist Amy Wagers, cardiologist Richard Lee of the Harvard-affiliated Brigham and Women?s Hospital in Boston, and their colleagues claim that a specific protein, GDF11, may explain young blood?s beneficial effects. They have reported that blood levels of GDF11 drop in mice as the animals get older and that injecting old mice with GDF11 can partially reverse age-related thickening of the heart. In two papers last year in Science, Wagers and collaborators also reported that GDF11 can rejuvenate the rodents? muscles and brains.

Last May, however, a group led by muscle disease researcher David Glass of the Novartis Institutes for Biomedical Research in Cambridge, Massachusetts, reported that the antibody the Harvard team used to measure levels of GDF11 also detected myostatin (also known as GDF8), a similar protein that hinders muscle growth. The Novartis group concluded from a different assay that GDF11 levels in blood actually rise with age in rats and people. And in their lab, GDF11 injections inhibited muscle regeneration in young mice.

Now, the Wagers and Lee group says the assay Novartis used to detect GDF11 and GDF8 was itself flawed. They found that the main protein detected by the antibody test is immunoglobulin, another protein that rises in blood level with age. Mice lacking the gene for immunoglobulin tested negative for the active form of GDF11/8 that the Novartis assay was thought to reveal, they report today online in Circulation Research.

?They actually had very consistent findings to ours with respect to the blood levels of GDF11/8 with the antibody we all used,? Wagers says. But ?their interpretation was confused by this case of mistaken identity.? A recently published study by University of California, San Francisco, researchers finding that GDF11/8 blood levels decline with age in people and are low in those with heart disease supports the contention that GDF11 has an antiaging role, her paper notes.

The Harvard team?s paper also disputes a recent study in which cardiac physiologist Steven Houser?s group at Temple University in Philadelphia, Pennsylvania, found that GDF11 injections have no effect on heart thickness in older mice. The problem, according to Wagers, is that commercially purchased GDF11 can vary in the actual level and activity of protein. ?It wasn?t something that affected us early on, but we figured out it was an issue,? she says. That lot-to-lot variability likely explains why the Houser group didn?t see any effects from GDF11 at the same apparent dose the Harvard group reported using, she adds. (Lee says his group now suspects that the dose was higher than they realized.)

To back up their earlier results, Wagers and collaborators again show in the new paper that daily GDF11 injections can shrink heart muscle in both old and new mice. But this time they note another observation: The mice also lost weight. ?We don?t have much insight into that right now, but we?re looking into it,? Wagers says. She says the findings suggest that as with other hormones, GDF11 may have ?a therapeutic window? for beneficial effects?too much may cause harm.

Houser says he agrees that one of the Novartis team?s assays for GDF11 was probably detecting immunoglobulin. But Houser notes that the group also used a different assay to detect GDF11 and that isn?t challenged by the new paper. (David Glass makes the same point.) Sorting out what role GDF11 may play in aging is important, Houser adds. ?I’m going to be 65 in a couple months. I’d love to have something that improves my heart, brain, and muscle function,? Houser says. ?I think the field is going to figure this out and this is another piece of the puzzle.?

Aging insidiously leaves its mark on our brains.

With age, our well-oiled neuronal machinery slowly breaks down: gene expression patterns turn wacky, the nuclear membrane disintegrates, and neatly organized molecules inside the cells break out of their segregated compartments, turning the intracellular environment into a maladaptive, muddled molecular soup.

Yet the aging phenomenon has been very tough to study. Historically, scientists relied on fast-aging animal models ? from fruit flies to primitive worms to mice ? to tease out the biological mechanisms of aging, especially for tissues that are hard to biopsy from patients, including the brain.

Despite the value of these reductionist models, many life-lengthening treatments fail in clinical trials, and the leap from flies to mice to men remains insurmountable.

With the rise of induced pluripotent stem cell (iPSC) technology, scientists have been able to transform patients? skin cells into iPSCs, which can then be coaxed into neurons for further study.

It?s a powerful technique: iPSCs derived from patients with Parkinson?s disease, for example, contain the same genetic underpinnings of the disease, which let scientists cheaply and efficiently test out theories and potential drug treatments?on human cells within the tightly controlled environment of a culture dish.

But the conversion process essentially turns back the clock: because iPSCs resemble early stage embryonic development, even when taken from an elder donor, they ? and the neurons generated from them ? lose their ?aged? signature. Previous research found that their epigenetic landscapes, which dictate what genes are expressed where via small chemical attachments to the DNA, are reset to match that of a younger cell?s profile during the reprogramming process.

For example, genes that promote cell division are jacked up, whereas genes involved in inflammation ? a strong correlate of aging ? are tuned down. This discrepancy hardly makes them a good model of their aged donors.

It?s a thorny problem that?s plagued the field for decades. But now, published last week in Cell Stem Cell, a team led by Salk Institute professor Dr. Fred ?Rusty? Gage has offered a clever solution.

The answer is to eschew iPSCs altogether, and take the road less traveled.

Using a method first discovered a few years ago at Stanford University, the team realized that with a series of careful biochemical tweaks, they could directly coax skin cells into fully functional neurons. Since these ?induced neurons? skipped the embryonic stage, they reasoned, maybe their age counters were not reset.

No one knew if and how cells created in this way differed from neurons that naturally aged in the human brain, says lead author Dr. Jermone Mertens.

To find out, the team took skin biopsies from 19 volunteers aged from infancy to 89 years old, and transformed those skin cells into neurons using both the iPSC method and the direct conversion approach.

They then compared these ?test tube neurons? to neurons obtained from autopsies of age-matched controls by looking at their transcriptomics ? that is, a bird?s eye view of gene expression patterns that change with age.

As expected, iPSC-generated neurons lost their life history, reverting back to a baby-like state.

In stark contrast, neurons generated by direct conversion significantly differed in their transcriptomes based on the donor?s age. ?They actually show changes in gene expression that have been previously implicated in brain aging,? said Mertens.

It?s a first, and it could be a game changer.

He pointed to a protein called RanBP17, which shuttles proteins in-and-out of the nucleus. The decline of RanBP17 was previously hypothesized to play a role in brain aging, but the theory was difficult to model in animals. However, to the team?s excitement, this abnormal decrease was recapitulated in neurons directly converted from older patients.

Other cellular assays also showed that the lab-grown neurons retained their telltale signs of aging. With age, the fragile membrane that separates the nucleus from other cellular component begins to fail, and proteins ? no longer confined to their physiological working space ? run amok.

This process could lead to aging or increase our susceptibility to age-related neurodegenerative disorders, but we don?t know, said Martens. He?s eager to put the new system to use. With this new culture system, we can now directly test these ideas, Martens said.

?The results are obviously going to have an impact,? agrees Dr. John Gearhart, an expert in regenerative medicine at the University of Pennsylvania, who wasn?t involved in the study.

Although the team only tried their cell-transforming method in neurons, Gage expects it to work for other organs as well, allowing scientists to create aged heart or liver cells. The technique could also be expanded to highly-structured 3D cultures such as organoids, and used to model aging human organs.

“We expect that the paradigm of direct conversion into age-equivalent cells can be very important for future studies of age-related diseases,” said Gage.

An unexpected factor may be influencing stem cell transplants, suggests a new study by researchers at the Stanford University School of Medicine. They found that a sleep deprived donor has a huge effect on the ability of blood and immune system stem cells to migrate to their proper spots in the bone marrow of a recipient.

The research was conducted on laboratory mice, but may have implications for human stem cell transplants. Thousands of procedures often referred to as bone marrow transplants (but more accurately called hematopoietic stem cell transplants) are performed every year.

In the experiment, a sleep deficit of only four hours could affect by as much as 50 percent the ability of stem cells to migrate successfully.

?Considering how little attention we typically pay to sleep in the hospital setting, this finding is troubling,? said Dr. Asya Rolls, an assistant professor at the Israel Institute of Technology, in a statement. ?We go to all this trouble to find a matching donor, but this research suggests that if the donor is not well-rested it can impact the outcome of the transplantation. However, it?s heartening to think that this is not an insurmountable obstacle; a short period of recovery sleep before transplant can restore the donor?s cells? ability to function normally.?

Rolls is co-lead author of the study along with Dr. Wendy Pang, a postdoctoral scholar at Stanford, and Dr. Ingrid Ibarra, the assistant director of the Stanford Cardiovascular Institute.

The team conducted research comparing mice who had been gently handled for four hours to prevent sleep with mice who were well-rested. They collected stem cells from the bone marrow of both groups of mice and injected them into 12 mice who had received what would normally be a deadly dose of radiation. The recipient mice also got a dose of their own bone marrow cells, so it would be possible to track the abilities of the donated cells in relation.

The researchers assessed the prevalence of myeloid cells, a type of immune cell, at both eight and 16 weeks after the transplant. They found that stem cells from the well-rested mice made up about 26 percent of myeloid cells over time, but stem cells from sleep deprived donors made up only about 12 percent of the recipient?s myeloid cells.

The team also looked at the ability of the stem cells to migrate properly from the blood into the bone marrow. After 12 hours, 3.3 percent of the stem cells from rested mice had found their way to the bone marrow, compared to only 1.7 percent of stem cells from sleepy mice.

Rolls and her colleagues found that the effects of sleep deprivation could be reversed by catching only a couple hours of sleep.

?Everyone has these stem cells, and they continuously replenish our blood and immune system,? Rolls said. ?We still don?t know how sleep deprivation affects us all, not just bone marrow transplant donors. The fact that recovery sleep is so helpful only emphasizes how important it is to pay attention to sleep.?