On Aug. 4, 1997, Jeanne Calment passed away in a nursing home in France. The Reaper comes for us all, of course, but he was in no hurry for Mrs. Calment. She died at age 122, setting a record for human longevity. Jan Vijg doubts we will see the likes of her again. True, people have been living to greater ages over the past few decades. But now, he says, we have reached the upper limit of human longevity. "It seems highly likely we have reached our ceiling. From now on, this is it. Humans will never get older than 115." his is the latest volley in a long-running debate among scientists about whether there's a natural barrier to the human life span. "It all tells a very compelling story that there's some sort of limit," said S. Jay Olshansky, who has made a similar argument for over 25 years. James W. Vaupel has long rejected the suggestion that humans are approaching a life span limit. He called the new study a travesty. "It is disheartening how many times the same mistake can be made in science and published in respectable journals," he said. Dr. Vaupel bases his optimism on the trends in survival since 1900.

But when Dr. Vijg and his students looked closely at the data on survival and mortality,they saw something different. The scientists charted how many people of varying ages were alive in a given year. Then they compared the figures from year to year, in order to calculate how fast the population grew at each age. The fastest-growing portion of society has been old people, Dr. Vijg found. In France in the 1920s, for example, the fast-growing group of women was the 85-year-olds. As average life expectancy lengthened, this peak shifted as well. By the 1990s, the fast-growing group of Frenchwomen was the 102-year-olds. If that trend had continued, the fastest-growing group today might well be the 110-year-olds. Instead, the increases slowed down and appear to have stopped. When Dr. Vijg and his students looked at data from 40 countries, they found the same overall trend. The shift toward growth in ever-older populations started slowing in the 1980s; about a decade ago, it stalled. This might have occurred, Dr. Vijg and his colleagues said, because humans finally have hit an upper limit to their longevity.

RG: Could you explain the research you did and the method you used in your analysis?

Vijg: We tested if human maximum life span is fixed or fluid and we found it to be fixed at around 115 years. We did this by looking at the maximum reported age at death in France, Japan, the United Kingdom and the United States. Firstly, we tested if improvement in survival also shifts to older age groups over time. We showed that improvement in survival in the oldest age group peaked in about 1980. This suggests - but does not prove - that we are reaching a maximum lifespan. Then we tested the maximum reported age at death since the 1960s. At first, this increased, but only up until the early 1990s. It then seemed to settle on a plateau, or even decline slowly, which is why we believe there is strong evidence that we have reached our ceiling.

RG: Why do you believe that humans have a natural age limit that is unlikely to be exceeded?

Vijg: Probably because the multiple longevity assurance systems humans have to prevent or fix damage and respond to stress are limited. This is also likely to be true for all animal species. A mouse lives much shorter than a human, possibly because it possesses inferior longevity assurance systems and can only get rid of damage and stress up until about three years.

Driven by technological progress, human life expectancy has increased greatly since the nineteenth century. Demographic evidence has revealed an ongoing reduction in old-age mortality and a rise of the maximum age at death, which may gradually extend human longevity. Together with observations that lifespan in various animal species is flexible and can be increased by genetic or pharmaceutical intervention, these results have led to suggestions that longevity may not be subject to strict, species-specific genetic constraints. Here, by analysing global demographic data, we show that improvements in survival with age tend to decline after age 100, and that the age at death of the world's oldest person has not increased since the 1990s. Our results strongly suggest that the maximum lifespan of humans is fixed and subject to natural constraints.

Individuals living at moderate altitudes (up to about 2000m) were shown to have lower mortality from coronary artery disease (CAD) and stroke (-22% and -12% per 1000m) and an about 50% lower risk of dying from Alzheimer's disease compared with their counterparts living at lower altitudes. In contrast, reported altitude effects on cancer mortality are still conflicting. However, due to shared risk factors, e.g. obesity and diabetes, in cardiovascular disease and cancer a shared biology for both disease entities may be assumed. Therefore, it is hypothesized that mortality from certain cancers will decline with increasing altitude as demonstrated for CAD. Altitude-dependent mortality from CAD, male colorectal cancer and female breast cancer from 2003 to 2012 in Austria has been evaluated based on data from the Austrian Mortality Registries (Statistik Austria). Since the phenomenon of migration was most pronounced towards larger communities (a population of greater than 20,000) only communities with a population below 20,000 were included to avoid important confounding from migration.

The general life expectancy, e.g. in 2009, increased from low altitude (less than 251m) to higher altitudes (1001 to about 2000m) by about 2 years, in males from 76.7 to 79.1 years and in females from 82.1 to 84.1 years. From low to higher altitudes, mortality rate from CAD decreased by 28% in males and by 31% in females. Mortality rate from male colorectal cancer and female breast cancer decreased almost linearly from low to higher altitude by 45% and 38%. Independent of altitude, increasing agriculture employment was associated with a diminished mortality from ischemic heart disease by about 15% for males and females. In contrast, solely increasing altitude was related to the reduction in cancer mortality.

The lower mortality from CAD at moderate altitudes is in close agreement with that reported from Switzerland. Reduced oxygenation at higher altitudes and altitude-related climate changes, e.g. temperature, UV radiation, and/or air-pollution but also differences in dietary behaviour were considered as potentially protective factors. Similarly, a set of altitude-dependent environmental and life-style factors have been suggested to contribute to lower mortality from Alzheimer's disease at higher altitudes. The present data extend preventive effects of living at higher elevations on male colorectal and female breast cancer mortality. The observation that more rural conditions may not have affected cancer mortality will even heighten the importance of altitude-specific effects. The nearly linear mortality reduction with increasing altitude strongly indicates a dose-response relationship.

Unfortunately, to date only little and conflicting information is available on cancer mortality at altitude. Given the fact of shared risk factors in cardiovascular disease and cancer the beneficial effects of moderate hypoxia stimuli at altitudes up to 2500m on cardiovascular risk factors might also contribute to the lowering of cancer mortality. For instance, obesity and diabetes are such shared risk factors which have recently been reported to be lower in US individuals living at higher altitudes. These authors speculated that cold-induced thermogenesis, decreased appetite, unintentional increased physical activity, and hypoxia-related better glucose tolerance could represent potential mechanisms explaining the inverse relationship between the prevalence of obesity and/or diabetes and altitude. The author of an ecological study attributed lower cancer death rates at higher places to elevated natural background radiation (hormesis theory) but emphasized that causal inferences cannot be made.

Besides changing climate conditions with increasing altitude a potentially higher exercise capacity in the altitude population helps to explain lower mortality. Whereas high-altitude regions like Leadville in Colorado (US) or the Altiplano in South America are rather flat, in the Alps the amount of hilly terrain increases steeply with altitude likely contributing to a higher fitness level in the altitude population. In the Swiss study a similar amount of physical activity in the low and higher altitude populations has been suggested. However, since the hilly terrain is much more challenging than the plain terrain, e.g. when walking or cycling, a similar amount of physical outdoor activities can result in higher exercise capacity in the altitude population. In any case, the remarkable protective effects of living at moderate altitudes also on cancer mortality are fascinating and deserve further investigation.

Genome-wide alterations in RNA expression profiles are age-associated. Yet the rate and temporal pattern of those alterations are poorly understood. Most often, age-associated physiological and molecular alterations are extracted using linear regression models. Linear regression assumes a constant change over time and therefore might be appropriate for organisms that aged over a short period. In humans, however, adulthood spans from 50 to 80 years. It is very unlikely that the rate of age-associated changes progresses at a constant rate. The fitness of different regression models to describe age-associated physiological features demonstrated that a quadratic or a parabolic regression model are most suitable to describe age-associated changes. Quadratic models have fewer assumptions compared with a linear model. Moreover, a quadratic model could be employed to identify the age when major changes occur (named here age-position). Using cross-sectional transcriptome studies, it was suggested that most transcriptional alterations in brain frontal cortex occur around the age of 42, and in Vastus lateralis muscle major changes occur already in the fourth decade. In both studies, two linear regression models were applied to identify the age-positions. Applying a quadratic regression model we indeed confirmed that major expression profiles are changed first in the fourth decade in both brain frontal cortex and Vastus lateralis muscle.

Ideally, the pattern of aging-associated molecular changes could be extracted from population-based datasets. These datasets are cross-sectional, covering a broad age-range, and all subjects are included. Most population-based datasets are skewed in the old age, making a linear regression model unfit. Here we investigated age-associated molecular changes in whole blood from two population datasets. The Rotterdam Study (RS) cohort III and the SHIP-TREND cohort were independently generated using RNA microarrays. After correcting for the skewed sample distribution across age, we demonstrate that an age-associated pattern of molecular changes is highly similar between the two datasets. We show that in whole blood major molecular changes occur only at the seventh decade, predominantly affecting the translation and immune cellular machineries.

The RS dataset was split into two subsets with the age of 65 years being selected as a cut-off point. At 65 years the age-position was found in the two age-matched datasets. The younger group (less than 65 years) comprised 606 individuals, whilst the older group (greater than 65 years) included 156 individuals. In the younger group, only 128 probes were found to be significantly age-associated and those were not enriched in any functional group. Those probes were not found among the overlapping genes between RS and SHIP-TREND datasets. This suggests that molecular changes in blood prior to 65 years are neither robust nor consistent. In contrast, in the older age group 1319 probes were age-associated and those were mapped to the immune system, translation and the defense response functional groups. 65% of those genes overlapped with the significant probes from the SHIP-TREND. This indicates that major expression profile alterations in blood occur from the seventh decade onwards. This age-position is in agreement with a recent study showing that the number of immune cells and T-cell receptor reduces from the seventh decade onwards.

Whether or not the rate of molecular aging is similar between tissues is poorly understood. In whole blood, we identified only a single age-position during the seventh decade. A single age-position was found in kidney cortex, also during the seventh decade. However, in brain frontal cortex and in Vastus lateralis muscle two age-positions were identified, the first during the fifth decade and a second one during early eighth decade. This suggests that in humans the age at which major molecular changes occur differs between tissues. This conclusion in agreement with physiological studies suggesting that the rate of age-associated tissue deterioration differs between tissues. Moreover, the prominent aging-associated gene networks also differ between tissues: translation and the immune system gene networks from blood were not identified in brain cortex or skeletal muscles tissues. An age-position could indicate an aging-associated disease risk for tissue-specific disorders and could be a consideration for treatments and interventions during aging.

In cases of severe ocular trauma involving the cornea, wound healing occurs following intervention, but at the cost of opaque scar tissue formation and damaged vision. Recent research has shown that mesenchymal stem cells (MSCs) are capable of returning clarity to scarred corneas; however, the mechanisms by which this happens remained a mystery. Researchers have now identified hepatocyte growth factor (HGF), secreted by MSCs, as the key factor responsible for promoting wound healing and reducing inflammation in preclinical models of corneal injury. Their findings suggest that HGF-based treatments may be effective in restoring vision in patients with severely scarred corneas. "Our results show that mesenchymal stem cells, in an inflamed environment, secrete high levels of HGF, which inhibit scar formation and restore corneal transparency. But if you silence the HGF expression, the stem cells lose their capacity to inhibit scar formation."

Trauma to the eye is the leading cause of corneal opacity, leading to 25 million cases of blindness annually. While injury is not a major cause of blindness, it is one of the most common causes of monocular blindness. Current treatments for corneal scarring vary from topical steroids to corneal transplantation. However, there are limitations to these treatments, including increased risk of infection and rejection of transplants. With the goal of better understanding why MSCs are capable of restoring clarity to scarred corneas, researchers used an animal model of ocular injury. They observed secretion of high levels of HGF from stem cells at the site of injury. Furthermore, the researchers showed that HGF is solely responsible for the restoration of corneal transparency - an observation that holds promise for developing HGF-based therapy for patients.

Molecular chaperone Heat Shock Protein 70 (Hsp70) plays an important protective role in various neurodegenerative disorders often associated with aging, but its activity and availability in neuronal tissue decrease with age. The compromised ability of neurons to express Hsp70 correlates with aging-related neurodegeneration. Here we explored the effects of intranasal administration of exogenous recombinant human Hsp70 (eHsp70) on lifespan and neurological parameters in middle-aged and old mice. Long-term administration of eHsp70 significantly enhanced the lifespan of animals of different age groups. Behavioral assessment after 5 and 9 mo of chronic eHsp70 administration demonstrated improved learning and memory in old mice. Likewise, the investigation of locomotor and exploratory activities after eHsp70 treatment demonstrated a significant therapeutic effect of this chaperone. Measurements of synaptophysin show that eHsp70 treatment in old mice resulted in larger synaptophysin-immunopositive areas and higher neuron density compared with control animals. Furthermore, eHsp70 treatment decreased accumulation of lipofuscin, an aging-related marker, in the brain and enhanced proteasome activity.

In summary, Hsp70 treatment extended mean and maximum lifespan, improved learning and memory in old animals, increased curiosity, decreased anxiety, and helped maintain synaptic structures that degrade with age. These results provide evidence that intranasal administration of Hsp70 could have significant therapeutic potential in preserving brain tissue and memory for middle-age and old individuals and could be applied either as unique self-contained treatment or in combination with other pharmacological therapies.

Pharmacologic blockade of the myostatin (Mstn)/activin receptor pathway is being pursued as a potential therapy for several muscle wasting disorders. The functional benefits of blocking this pathway are under investigation, in particular given the findings that greater muscle hypertrophy results from Mstn deficiency arising from genetic ablation compared to post-developmental Mstn blockade. Using high-resolution mass spectrometry coupled with SILAC mouse technology, we quantitated the relative proteomic changes in gastrocnemius muscle from Mstn knockout (Mstn-/-) and mice treated for 2-weeks with REGN1033, an anti-Mstn antibody.

Relative to wild-type animals, Mstn-/- mice had a two-fold greater muscle mass and a greater than 1.5-fold change in expression of 12.0% of 1137 quantified muscle proteins. In contrast, mice treated with REGN1033 had minimal changes in muscle proteome (0.7% of 1510 proteins with more than a 1.5-fold change, similar to biological difference 0.5% of 1310) even though the treatment induced significant 20% muscle mass increase. Functional annotation of the altered proteins in Mstn-/- mice corroborates the mutiple physiological changes including slow-to-fast fiber type switch. Thus, the proteome-wide protein expression differs between Mstn-/- mice and mice subjected to specific Mstn blockade post-developmentally, providing molecular-level insights to inform mechanistic hypotheses to explain the observed functional differences.

Neurons communicate by sending impulses, in the form of secretion of neurotransmitters, across small spaces called synapses. It is these synapses that undergo structural and functional changes during formation and retrieval of memories. Though alterations in synaptic performance are believed to accompany aging, the causal relationship between age-dependent memory impairment and synaptic changes remains largely unknown. Using the fly Drosophila melanogaster as a model, we found that feeding them spermidine - a polyamine compound - suppresses age-induced decline in olfactory memory, providing us with a tool to further decipher mechanisms associated with age-dependent memory impairment.

In this study, we investigated the relationship between synaptic changes and age-dependent memory impairment by studying the olfactory circuitry. We observed an age-related increase in the levels of the synaptic proteins Bruchpilot and Rim-binding protein, which caused an enlargement of the presynaptic active zone - the complex of proteins that mediate neurotransmitter release - and enhanced synaptic transmission. Interestingly, feeding of spermidine was sufficient to abolish these age-associated presynaptic changes, further emphasizing the relationship between presynaptic performance and age-dependent memory impairment. Furthermore, flies engineered to express an excess of the core active zone protein Bruchpilot showed a premature impairment in memory formation in young flies. Based on our data, aging plausibly steers the synapses towards the upper limit of their operational range, limiting synaptic plasticity and contributing to impairment of memory formation.

Go to any health food store and you're likely to see shelves crowded with antioxidants that promise to quell damage from free radicals, which are implicated in a myriad of human diseases and in the aging process itself. The problem is that antioxidants have failed to show benefits in several clinical trials and there is even some evidence they could be counterproductive. The current approaches to free radicals may fail because they apply a "sledgehammer" to a complex metabolic process that provides essential energy to our cells. Free radicals are produced in the mitochondria - the energy-converting organelles which are abundant in almost every type of human cell. Highly-reactive free radicals, which oxidize cell constituents (hence the use of antioxidants), are spun-off as a normal byproduct of cellular bioenergetics; it's a process that appears to go up when cells are stressed, something that can occur with aging and disease.

A chain of electron transporters within the mitochondria is involved in the production of both free radicals and the chemical energy essential for life. The challenge has been to stop the free radicals without shutting down the cell's ability to release energy. Researchers did that by painstakingly screening 635,000 small molecules to single out the few that blocked free radical production at a specific site thought to be a major source of free radicals in the electron transport chain. In this latest research, they demonstrated the potency and specificity of the successful molecules and tested their effects in cell culture, isolated hearts, and live models of disease. The compounds dramatically protected against reperfusion injury in a mouse heart model of ischemia. "Most of the lasting damage from heart attacks comes when blood flow is restored to the heart muscle. These compounds have great potential as therapeutic leads for drugs that could be given following a heart attack or after stents have been inserted to open blocked coronary blood vessels." In addition, the molecules diminished oxidative damage in brain cells cultured in low levels of oxygen; they also diminished stem cell hyperplasia in the intestines of fruit flies.

The study offers researchers a way to test the hypothesis that oxidative damage is specifically linked to disease. "For the first time we can test the effects of free radical damage in Alzheimer's, Parkinson's, cancer, type 2 diabetes, macular degeneration - you name it. It gives you a target, and a drug candidate to hit that target. We can start to answer questions that scientists have puzzled about for 50 years in terms of the specifics of oxidative damage. We now have a precise tool to find out if the theory is correct. We can go into a biological system, see specifically what free radicals do and take preliminary steps to stop it."

How can we overcome our niggling suspicion that there is something dubious, if not outright wrong, about wanting to live longer, healthier lives? And how might we pursue longer lives without at the same time falling prey to quasiscientific hype announcing imminent breakthroughs? In order to understand why aging is changing, and what this means for our futures, we need to learn more about the aging process itself. As a biologist who specializes in aging, I have spent more than four decades on a quest to do exactly this. Not only have I asked why aging should occur at all (my answer is encapsulated in a concept called disposability theory), but I have also sought to understand the fastest-growing segment of the population - those aged 85 and above. The challenges inherent in understanding and tackling the many dimensions of aging are reflected in a clutch of new books on the topic. Are these books worth reading? Yes and no. They take on questions like: Can we expect increases in human longevity to continue? Can we speed them up? And, on the personal level, what can we do to make our own lives longer and healthier? If nothing else, these books and their varied approaches reveal how little we actually know.

To find out more about factors that can influence our individual health trajectories across ever-lengthening lives, my colleagues and I began, in 2006, the remarkable adventure of the still ongoing Newcastle 85+ Study, an extremely detailed investigation of the complex medical, biological, and social factors that can affect a person's journey into the outer reaches of longevity. For each individual, we determined whether they had any of 18 age-related conditions (e.g., arthritis, heart disease, and so on). Sadly, not one of our 85-year-olds was free of such illnesses. Indeed, three quarters of them had four or more diseases simultaneously. Yet, when asked to self-rate their health, an astonishing 78 percent - nearly four out of five - responded "good," "very good," or "excellent." This was not what we had expected. The fact that these individuals had so many age-related illnesses fit, of course, with the popular perception of the very old as sadly compromised. But the corollary to this perception - that in advanced old age life becomes a burden, both to the individuals themselves and to others - was completely overturned. Here were hundreds of old people, of all social classes and backgrounds, enjoying life to the fullest, and apparently not oppressed by their many ailments.

As for my stake in the enterprise, I began investigating aging when I was in my early 20s - well before I had any sense of my own body aging. Quite simply, I was curious. What is this mysterious process, and why does it occur? Everything else in biology seems to be about making things work as well as they can, so how is it that aging destroys us? Now that I am growing older myself, my research helps me understand my own body and reinforces the drive to live healthily - to eat lightly and take exercise - though not at the cost of eliminating life's pleasures. For all that I have learned about aging, my curiosity remains unabated. Indeed, it has grown stronger, partly because as science discovers more about the process, it reveals that there is ever more to learn, ever greater complexity to unravel, and partly because I am now my own subject: through new physical and psychological experiences in myself, I learn more about what older age is really like. I know all too well that the next phase of my life will bring unwelcome changes, and of course it must end badly. But the participants of the Newcastle 85+ Study have shown me that the journey will not be without interest.

Organovo today announced its plan to develop 3D bioprinted human liver tissue for direct transplantation to patients. The company is announcing its program to develop this therapeutic tissue based on the achievement of strong results in preclinical studies in animal models showing engraftment, vascularization and sustained functionality of its bioprinted liver tissue, including stable detection of liver-specific proteins and metabolic enzymes. Organovo expects to pursue this opportunity with a formal preclinical development program. For patients in need of a liver transplant, no robust alternatives exist today. Approximately 17,000 patients are on the U.S. liver transplant waiting list, and only 6,000 liver transplants are performed each year. Organovo plans to develop clinical solutions in two initial areas. First, acute-on-chronic liver failure is a recognized and distinct orphan disease entity encompassing an acute deterioration of liver function in patients with liver disease, which affects 150,000 patients annually in the United States. Second, pediatric metabolic liver diseases represent another orphan disease indication where a bioprinted liver tissue patch may show therapeutic benefits.

"We're excited to introduce an implantable bioprinted liver tissue as the first preclinical candidate in our therapeutic tissue portfolio, and see the early results as extremely promising. The scientific and commercial progress we have already made with engineered human liver tissue in drug toxicity testing has given us a firm foundation upon which to build a larger tissue for transplant. Advancing our first therapeutic tissue into preclinical development is an important milestone for Organovo, and we believe that 3D bioprinted tissues have an opportunity to provide options for patients who suffer from liver disorders. Organovo's approach is designed to overcome many of the challenges that cell therapies and conventional tissue engineering have struggled to address, including limited engraftment and significant migration of cells away from the liver. In our preclinical studies, we deliver a patch of functional tissue directly to the liver, which integrates well, remains on the liver and maintains functionality. We believe our tissues have the potential to extend the lives of patients on liver transplant lists, or those who do not qualify for transplants due to other factors."

Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are all characterized by clumped, misfolded proteins and inflammation in the brain. Researchers have discovered that these processes may be triggered by proteins made by our gut bacteria (the microbiota). Their research has revealed that exposure to bacterial proteins called amyloid that have structural similarity to brain proteins leads to an increase in clumping of the protein alpha-synuclein in the brain. Aggregates, or clumps, of misfolded alpha-synuclein and related amyloid proteins are seen in the brains of patients with the neurodegenerative diseases AD, PD and ALS.

Alpha-synuclein is a protein normally produced by neurons in the brain. In both PD and AD, alpha-synuclein is aggregated in a clumped form called amyloid, causing damage to neurons. Researchers hypothesized that similarly clumped proteins produced by bacteria in the gut cause brain proteins to misfold via a mechanism called cross-seeding, leading to the deposition of aggregated brain proteins. They also proposed that amyloid proteins produced by the microbiota cause priming of immune cells in the gut, resulting in enhanced inflammation in the brain. The research involved the administration of bacterial strains of E. coli that produce the bacterial amyloid protein curli to rats. Control animals were given identical bacteria that lacked the ability to make the bacterial amyloid protein. The rats fed the curli-producing organisms showed increased levels of alpha-synuclein in the intestines and the brain and increased cerebral alpha-synuclein aggregation, compared with rats who were exposed to E. coli that did not produce the bacterial amyloid protein. The curli-exposed rats also showed enhanced cerebral inflammation.

Similar findings were noted in a related experiment in which nematodes (Caenorhabditis elegans) that were fed curli-producing E. coli also showed increased levels of alpha-synuclein aggregates, compared with nematodes not exposed to the bacterial amyloid. "These new studies in two different animals show that proteins made by bacteria harbored in the gut may be an initiating factor in the disease process of Alzheimer's disease, Parkinson's disease and ALS. This is important because most cases of these diseases are not caused by genes, and the gut is our most important environmental exposure. In addition, we have many potential therapeutic options to influence the bacterial populations in the nose, mouth and gut."

In the United States, over 1.5 million osteoporotic fractures occur annually. The majority of these occur in the latter decades of life when rates of bone loss and microarchitectural deterioration are at their greatest. Exercise is a commonly recommended intervention for preventing bone fragility; however, human and animal studies suggest that the anabolic effect of exercise is much less potent in the mature and post-mature vs. the immature skeleton. These observations raised the question: is exercise a worthwhile strategy for promoting bone health in mature and elderly individuals? One author cites minuscule gains in bone density reported from exercise trials in adult populations and concludes that "exercise has little or no effect on bone strength." This conclusion, however, is based on studies that do not take into account recent advances in non-invasive technologies for measuring bone density and structure or new strategies to make exercise more potent, or osteogenic, in aging populations.

Human studies have demonstrated an age-related decline in the responsiveness of bone mineral density (BMD), as measured by dual-energy X-ray absorptiometry (DXA), to exercise interventions. Nevertheless, a recent meta-analysis in older adults revealed small but statistically significant increases in BMD at the lumbar spine and femoral neck. It is important to consider, however, the inherent limitations of DXA that may lead to underestimation of the mechanical benefits of exercise. Based on attenuation of photons by bone and soft tissue, DXA provides a precise estimate of the amount of bone located within an area; however, it does not reveal bone structure. Recent introduction of quantitative computed tomography (QCT), DXA-derived hip structural analysis (HSA), and magnetic resonance imaging (MRI) has afforded the ability to assess bone geometry, bone macro- and micro-structure, three-dimensional bone density, and estimates of bone strength using engineering analyses. A systematic review of studies using either peripheral QCT (pQCT) or HSA to measure exercise effects on bone strength across various age groups reported improvements of 1-8% in children and adolescents, with either no change or very modest improvements in middle-aged and older adults. Nevertheless, like DXA, HSA and pQCT have inherent limitations that make exercise studies difficult to interpret.

Multiple lines of evidence from human and animal studies indicate that the aging skeleton remains modestly responsive to exercise interventions. Animal and human studies demonstrate that mature and senescent bone retains the ability to respond to loading with osteogenesis. Clearly, further mechanistic research is needed to fully elucidate why bone becomes less sensitive to exercise with age. Innovative paradigms such as rest insertion and "non-customary" loading may be necessary to maximize the osteogenic potential of exercise. Further, studies suggest that the sympathetic nervous system may be an important mechanistic link between physical activity and bone health. This emerging evidence raises the possibility that pharmacological intervention may be able to augment the benefits of exercise on bone health in humans across the lifespan.

Researchers have created what they call "hyperelastic bone" that can be manufactured on demand and works almost as well as the real thing, at least in monkeys and rats. Though not ready to be implanted in humans, bioengineers are optimistic that the material could be a much-needed leap forward in quickly mending injuries ranging from bones wracked by cancer to broken skulls. The scaffold is simpler to make than others and it offers more benefits. Surgeons currently replace shattered or missing bones with a number of things. The most common option is an autograft, where a piece of bone is taken from a patient's own body, usually from a hip or a rib, and implanted where it's needed elsewhere in that same patient's skeleton. Surgeons prefer autografts because they're real bone complete with stem cells that give rise to cartilage and bone cells to provide extra support for the new graft. (Humans can't regrow entire skeletons from scratch with stem cells, but existing bone can signal stem cells where to grow and what to grow into.) What's more, because the new bone replacement comes from a patient's own body, there's no risk of immune rejection. But only so much of a person's skeleton is available for grafting, and doing so tacks on another painful surgery and recovery for the patient.

Another bone replacement option is creating a scaffold for bone to grow on. These scaffolds, made of both natural and synthetic materials, work like the framing of a building. When inserted into the body, stem cells latch onto the structure and differentiate into cells that start to build bone, much as construction workers assemble walls, floors, and glass around a skyscraper's steel girders. Or, at least, that's how it should work - unlike in an autograft, stem cells don't always turn into the needed bone or cartilage because of the scaffolds' material makeup. To make matters worse, the immune system occasionally sees these scaffolds as foreign and attacks them, preventing any bone growth at all. And if a scaffold is to be used to regenerate small bones, such as many of those found in the face, for example, doctors worry that it would take too much time and money to make them. The new hyperelastic bone is a type of scaffold made up of hydroxyapatite, a naturally occurring mineral that exists in our bones and teeth, and a biocompatible polymer called polycaprolactone, and a solvent. Hydroxyapatite provides strength and offers chemical cues to stem cells to create bone. The polycaprolactone polymer adds flexibility, and the solvent sticks the 3D-printed layers together as it evaporates during printing. The mixture is blended into an ink that is dispensed by the printer, layer by layer, into exact shapes matching the bone that needs to be replaced. The idea is, a patient would come in with a broken bone and instead of going through painful autograft surgeries or waiting for a custom scaffold to be manufactured, he or she could be x-rayed and a 3D-printed hyperelastic bone scaffold could be created that same day. Because the ink materials - that is, hydroxyapatite along with the polymer and solvent - are commonly used in biomedical engineering labs, hyperelastic bone would be cheap to print.

To test their material, the team first tested their 3D-printed scaffold as a material to fuse spinal vertebrae in rats. Their goal was to see whether their material could lock two adjacent vertebrae in place as well as other scaffolds commonly used to treat spinal injury patients. Eight weeks after the researchers implanted the hyperelastic bone, they found that new blood vessels had grown into their scaffold - a necessary step to keep bone-forming tissue alive - and calcified bone started to form from the rats' existing stem cells. The combination fused the vertebrae more efficiently than the controls that received either a bone graft from a donor or nothing at all. The researchers also used hyperelastic bone to repair a macaque monkey's damaged skull. After 4 weeks with a hyperelastic bone implant, the scaffold was infiltrated with blood vessels and some calcified bone. Equally important, the macaque didn't suffer from any adverse biological effects, such as inflammation or infection, that many synthetic implants can cause.