Fight Aging! Newsletter, October 10th 2016

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • 2016 Year End SENS Rejuvenation Research Fundraising: Fight Aging! will Match the Donations of New SENS Patrons
  • How to Go About Using Myostatin Antibodies to Grow Muscle Today
  • A Discussion of Natural Limits on Lifespan, for Some Definition of Natural
  • Populations at Moderate Altitude Have Lower Rates of Some Age-Related Diseases
  • Investigating the Rate at which RNA Expression Changes with Age
  • Latest Headlines from Fight Aging!
    • Better Understanding how Cell Therapy can Clear a Scarred Cornea
    • Heat Shock Protein Delivered as a Therapy Slows Aging in Mice
    • Different Results from Myostatin Antibodies versus Myostatin Knockout
    • Spermadine Grants Insight into a Mechanism of Age-Related Memory Dysfunction
    • A Different Approach to Reducing Mitochondrial Oxidants
    • An Example of the Glaring Lack of Ambition in Aging Research
    • Progress Towards a Bioprinted Liver Patch for Transplantation
    • Theorizing on the Contribution of Gut Bacteria to Neurodegeneration
    • To What Degree Does Exercise Strengthen Bones or Slow Age-Related Bone Loss?
    • Bioprinting Bone Scaffolds to Guide Regrowth

2016 Year End SENS Rejuvenation Research Fundraising: Fight Aging! will Match the Donations of New SENS Patrons

As I mentioned not so long ago, and starting on November 1st, Fight Aging! will be doing something a little different in 2016 to support the end of year SENS rejuvenation research charitable fundraising efforts coordinated by the SENS Research Foundation staff. I would hope that I don't have to repeat to the audience here just how important this work is to the future - for ourselves, our descendants, for humanity as a whole. Aging is by far the greatest cause of suffering and death in the world, and we stand on the verge of being able to treat and prevent the causes of aging. Yet we live in a society of bread and circuses in which medical research is given little attention and little funding in comparison to the benefits it can bring. Medical research for aging receives but a tiny fraction of that pittance. Most of the important lines of work leading to human rejuvenation through repair of the cell and tissue damage that causes aging are still near-completely funded by philanthropy, through the foresight and generosity of communities like ours. If we can push things forward to the point at which they are picked up by established funding sources, that is a victory, one that leads to companies and products in development. We have achieved that for some types of rejuvenation therapy, but more must be accomplished yet.

So we in the grassroots have all been pitching in for years now, nearing a dozen fundraisers by my count, and this year we saw the big leap ahead represented by Michael Greve's 10 million pledge - a significant step forward. It was also a year in which we found smaller fundraisers more of a challenge than in the recent past. Donor fatigue is a real concern; the new crowdfunding platforms are an amazing tool, but reaching out several times a year produces diminishing returns. We've been taking things project by project and year by year in an ad-hoc manner, each its own effort, a new outreach. This is a long race of many years, however, not a series of sprints. The SENS Research Foundation's new Project|21 initiative should remind us of that, as their goalposts are explicitly set five years out, with a lot of implicit followup to continue on from there. Similarly for those of us who have invested in startups working on SENS technologies this year and last: a biotechnology startup is a project that comes to fruition in its own time, and that is likely five years or more in the average case. So perhaps we advocates banging the drum in the grassroots need to slow down a little and set up for the longer haul in our initiatives.

It is with this sort of thinking in mind that Josh Triplett, whom you may recall generously aided in setting up the 2015 matching fund, and I are each putting up 12,000 to encourage existing supporters and new arrivals to become SENS Patrons: to set up recurring monthly donations to the SENS Research Foundation. This will start when this year's SENS Research Foundation end of year initiative starts, on November 1st, and this Fight Aging! support will slot into that broader effort. Starting on November 1st, from the 24,000 fund Josh and I will match a year of donations for anyone who becomes a SENS Patron by creating a new recurring donation. We think that this is a good way to help set up a solid of philanthropic grassroots support. Take a moment to look back at the history of the our community, all the way back to the launch of the Methuselah Foundation's 300, a group of people pledging monthly donations to the organization. The 300 initiative was instrumental in launching the Methuselah Foundation, and thus also instrumental in launching the first SENS research programs years before the SENS Research Foundation spun off into its own organization. The 300 remain an important part of the Methuselah Foundation's support today, providing a solid core of funding for a range of projects, including rejuvenation research. That is a good thing to emulate, we think.

This 24,000 is a start, not the final word. We are looking for additional supporters willing to add their weight to this SENS Patrons matching fund. If you are interested please do contact me. The more people to put their shoulder to the wheel, the faster it turns. The way that organizations become attractive enough for high net worth donors to write seven figure checks is for there to be a large crowd at the gates, demonstrating their support. When it comes to philanthropy, wealth always follows the enthusiasm of the crowds, and it is the role of advocates and early donors to help draw in those crowds, to persuade ordinary folk just like you and I that this business of rejuvenation biotechnology is serious, plausible, and, given the funding, imminent. Bootstrapping a movement is always hard, but in this case the payoff is truly enormous. We are entering the era in which money can buy additional years of healthy life, which today means paying for progress in the right lines of medical research, and we can help to make it happen.

How to Go About Using Myostatin Antibodies to Grow Muscle Today

Lower levels of myostatin activity, achieved either through genetic engineering or blockade via antibodies, cause muscle growth. In the former case, where individuals lack functional myostatin throughout their lives, the result is lot of additional muscle growth; twice as much muscle tissue, or more. In the latter case the effects are smaller, but still significant. A short course of myostatin antibody treatment in mice added 20% extra muscle mass, and in humans a six month trial in elderly people added a measurable amount of additional muscle, while improving functional measures that typically decline dramatically in later age. There are a range of animal species in which it is possible to find established heavily muscled lineages with myostatin loss of function mutations of one sort or another: dogs, cows, and mice, the mutation either naturally occurring or created in the laboratory. There are even a few humans in the naturally occurring category.

Given the large numbers of myostatin-deficient animals, the extensive data on those animals, and results from human trials and the run up to those trials, it seems that manipulating one's own myostatin activity as an enhancement is something to look into for the near future. As in why don't we set out to try this today? Extra muscle with no effort is probably a nice to have for the younger folk in the audience, but the real application here is as a compensatory therapy to meaningfully delay the onset of physical frailty in older age. It doesn't solve any of the underlying issues that cause loss of muscle mass and strength with age, but it does appear to help a great deal more than other approaches are likely to at the present time, and is additive with those approaches. Young people can always substitute time and willpower for technology on the additional muscle front, but that option fades in effectiveness in later life - the returns on investment diminish greatly as age-related degeneration accelerates.

Viable myostatin or related follistatin and smad7 gene therapies for adults are a few years away yet, I think, pending a robust solution to tissue coverage. Methodologies must be developed to reliably ensure that therapies edit the genome in enough cells to be effective, but this is a challenge for everyone in the industry. It will not go unsolved for long now that CRISPR-based gene editing is a going concern. Still, a few years from now is not today. The antibody approach on the other hand is something that could be carried out today, if you had a reliable supply, dosage information, and the necessary materials to self-administer via injections. Give this list of ingredients, all of which are out there, I'm fairly certain that a range of individuals are already quietly doing exactly this. It will be the usual suspects, a mix of professional athletes and forward-thinking folk with laboratory experience and access. So why not forward-thinking older people as well?

The immediate raw materials to hand consist of research papers, study results, and suppliers of myostatin antibodies. From the research papers and study results one can obtain the particular brand of antibodies used and the dosages and treatment duration. There are a number of suppliers, such as Abcam, or take your pick of the dozens of others. Not all of which are providing a product that is appropriately useful in this context, of course. Not all suppliers sell to just anyone in this modern world of regulations and the drug war, either. Ideally you would pick the same antibody source as was used in one or more papers, and for preference the exact one used in a human trial. Human trials, however, have a way of being associated with specific companies, and they will probably be making their own, or exclusively licensing someone else's product. Regardless, there are choices, and a choice can be made. But most importantly, one has to verify that the supplier is actually delivering something that works.

At this point it would be prudent to obtain access to a laboratory and run tests. In our community there are a number of groups with the connections to kick that off. Let us say, for the sake of argument, a group buy organized by Longecity with additional fundraising to pay for the labs used by the Major Mouse Testing Program to validate that the product works in mice. There are three or four other organizations that could substitute in for either of those. The testing could even be structured to obtain useful scientific data in older mice, perhaps, which is something that seems a little less well exercised than the use of myostatin antibodies in younger mice. Overall that should not cost more than a few tens of thousands if picking a thrifty organization, and nor should it take more than a few months once the money is in hand.

There are matters other than the purely technical to be dealt with, however. Somewhere along the way the aforementioned prudent individual will engage a lawyer or two to figure out which part of buying the antibodies and injection kits and then self-administering is illegal or otherwise risky in the present jurisdiction. This will probably cost as much as the testing, which is a sad statement on the priorities of this fallen world of ours. This is the drug war age, and anything involving needles and biotechnology that falls outside the bounds of medical practice is at the least something that will raise the odds of attention from unwanted quarters. No purchase goes unmonitored for some types of apparatus, and injection kits are no doubt on that list. Further, everything involving medicine tends these days to operate on a forbidden unless explicitly allowed model, more is the pity. So all in all there is, as ever, a large difference between what one can do with little effort and what is prudent to do on one's own, without support or forethought.

Still, it seems to me that this is a viable project to explore further. The technology appears to have a good expectation of positive results given the human and extensive animal data to date, provided that the right tools are used, and there is a lot of data to establish dosages and the right products to use. The plausible worst outcome from an investigation of the legalities is likely to be along the lines of "contract the injecting to a clinic in Mexico or Canada." The whole exercise of research and validation outlined above is well within the capability of a motivated group of people pitching in a few thousand each. The parts where it might cheerfully fall apart are in the cost of the desired antibodies, or in establishing a relationship with a supplier willing to go along with a group of people who are self-administering. That will no doubt make their legal teams nervous. It might be necessary to add an intermediary clinic or laboratory to the mix regardless of the formal legal status of the activities.

But you don't know unless you try.

A Discussion of Natural Limits on Lifespan, for Some Definition of Natural

A recently published analysis of the nature of limits to human life span under our present rapidly changing circumstances is receiving a lot of press attention today. The press being the press, you might skip the popular science articles in favor of the paper. Since it is not open access, you'll have to obtain it from the usual unofficial sources. It is an interesting read, and serves as a reminder that the research community actually knows very little about the demographics of aging at very advanced age. The data is so sparse past age 110 that the statistics of mortality, very reliable in earlier old age, rapidly turn into a sludge of uncertainty. It is possible at this point in time to argue either side of the position that there is or is not a limit to longevity under present circumstances, though most of us probably think that one or the other side is weak. On the one hand we can theorize that maximum human life span is increasing, in a way analogous to the fact that life expectancy at 60 is inching upward at a year every decade, but more slowly, and we might suggest the data for extreme old age is so bad that the ongoing change can't be identified. On the other hand we can instead theorize that there is some limiting process that hasn't changed at all over the course of recent human history, is not impacted meaningfully by modern medicine, plays a very large role in supercentenarians in comparison to younger old people, and renders mortality rates so very high at the extremes of human life spans as to form a limit.

This is actually a point worth making twice: when limits to lifespan are discussed, we're not talking about actual limits per se, but effective limits. A very large mortality rate, possibly coupled with rapid growth in mortality rate over time, looks a lot like a hard barrier to further progress in practice, but there is still the chance that someone could beat the odds. Where the data for supercentenarians is good enough to fill in tentative mortality rates with large error bars, up to age 115, that rate is around 50% annually. The mortality rate may increase greatly after that point, and that would be entirely expected given the absence of more than the one certified example making it past 120, but it is very unclear from the limited data. Mortality rates reflect actual physical processes, the accumulation of forms of cell and tissue damage that cause the suffering, death, and disease of old age. The damage is the same, but the proximate causes of death for supercentenarians are quite differently distributed from those of younger old people, prior to a century of age. The majority appear to be killed by transthyretin amyloidosis that clogs up the cardiovascular system, and that is becoming known to play a much lesser - but still significant role - in heart disease in earlier old age. Could this form of amyloidosis be the candidate for a process that is not all that affected by the past century of changes in medicine and lifestyle, and that becomes much more important in extreme old age than early old age? Possibly. The only way to know for sure is to build ways to clear this form of amyloid and see what happens.

The natural state of aging is a function of damage and how medicine addresses that damage - which is poorly and next to not at all at the present time. Almost all medicine for age-related conditions fails to address their root causes, the cell and tissue damage of aging, and takes the form of patching over that damage in some way or coaxing biological machinery to cope slightly better with running in a damaged environment. Predictably it is expensive and only marginally effective in comparison to true repair. As above in the comments on amyloidosis, find a way to repair that problem and life span will increase, as the machinery of biology will be less damaged and less worn down into high rates of failure. That is the point to take away from this discussion. It has to be said that the lead of the study, Jan Vijg, comes across as very pessimistic on aging in his comments here when considered in comparison to past remarks and collaborations with SENS folk that I've seen from him. That is the case even granting that he is in the camp of researchers who believe there is no alternative to a very slow and expensive reengineering of human metabolism in order make incremental gains in life span and slowing of the aging process.

What's the Longest Humans Can Live? 115 Years, New Study Says

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.

Human lifespan may have maxed out

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.

Evidence for a limit to human lifespan

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.

Populations at Moderate Altitude Have Lower Rates of Some Age-Related Diseases

Correlations are everywhere, and not all of them are meaningful. Here I'll point out a short open access paper, in PDF format only at the moment, that outlines an interesting relationship between population altitude, mortality rate, and incidence of common age-related conditions. In short, people at higher altitudes have modestly better long term health and a few years of additional life expectancy when compared with those closer to sea level - a fairly interesting outcome, and one that might spur speculation. It has to be said that there are a number of fairly straightforward relationships between location and longevity. In many cases these are fairly obviously connected to wealth. If you look at wealthier regions, you find people who benefit from that wealth: greater access to medical technology and information about health, the education and will to use those resources, and all of the other matters of status, intelligence, and so forth that are linked with wealth in a web of correlations. If you look at smaller wealthier locations, you find selection and migration effects in which those already tending to greater longevity due to their greater wealth move there.

In the case of altitude, however, wealth isn't an obvious factor, one that might be used to explain greater health and longevity at higher elevations. The authors of this paper reach instead for greater levels of exercise as a likely factor, which is reasonable given the geography of the regions under study. Exercise and diet have two of the largest effects when it comes to natural variations in health and longevity, so thinking about how to use them to explain this sort of data is usually the best approach. As always, bear in mind that I point out papers of this nature because the subject is interesting, not because it is of any practical use whatsoever. Small variations of a few years up or down are unimportant, and the gains you can obtain from exercise and calorie restriction are only worth chasing because they cost nothing but time and the expected outcome is both reliable and backed by a large amount of scientific evidence, which is more than can be said for anything else you can do right now, this instant. The future of longevity for all of us is overwhelmingly determined by progress in medical science, the construction of rejuvenation therapies capable of repairing and reversing the causes of aging. The more of that taking place, the better off we are and the longer we live in good health. Even first generation therapies should extend human life to a much greater degree than just the few years of difference noted in this paper.

Lower mortality rates in those living at moderate altitude

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.

Investigating the Rate at which RNA Expression Changes with Age

Epigenetics is the study of mechanisms that change the pace at which proteins are produced from the blueprints encoded in DNA, a process known as gene expression. The first step in gene expression is the generation of RNA, which is what is actually usually measured. Rates of production - and thus numbers of specific RNA and protein molecules in circulation - are the switches and dials that control cellular processes. These rates of production change constantly, as the various processes of production and activities of molecular machinery interact with one another in response to internal and external circumstances. Researchers have in recent years discovered that they can identify more stable patterns of changes in the noise, patterns that correspond to age. This is promising on many levels. On the practical front it is a path to biomarkers of aging that accurately reflect biological rather than chronological age, and thus can be used to greatly speed up the assessment and develoment of rejuvenation therapies. When it comes to fundamental research, patterns of epigenetic alterations to the production of biomolecules are another tool by which the course of aging and its mechanisms can be mapped.

It is fairly well established that most natural genetic variations are only important to health and mortality in later life, and even then only collectively. Individual genetic variants have tiny effects and very few are consistent across study populations. Young people see no measurable impact, but when old, with a high level of cell and tissue damage, many gene variants grant small, differing levels of protection or accommodation of damage. Obviously these are not large effects on the whole: the best of combinations raises the odds of living an extremely long life from minuscule to merely tiny, and beneficiaries are still frail and dependent at the end, crushed by high levels of damage in the biological machinery that sustains life.

If genetic variants are only really important in later life, then should we also expect the pace of change in epigenetic patterns and rates of gene expression to be much higher in later life? At the very high level, and even from simple metrics like activity, skin elasticity, and grip strength, we know that aging isn't a linear process. It is a downward spiral that proceeds ever faster as damage feeds on damage, and the final collapse into terminal ill health at the end of life is often a rapid thing after years of much slower decline. It would be surprising if measures that truly reflect the progression of mechanisms of aging turned out to show something different. In this paper, the researchers look at the RNA levels resulting from gene expression, and use statistical methods to mark the ages at which more significant changes start, going gene by gene to build the beginning of a picture. They find that most of the identifiable and robust changes occur in old age.

Blood RNA expression profiles undergo major changes during the seventh decade

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.

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Better Understanding how Cell Therapy can Clear a Scarred Cornea

Researchers here make some progress in understanding how stem cell therapies can reduce scarring in a damaged cornea. While focused on injuries rather than age-related damage, this should hopefully still speed progress towards better therapies for a range of conditions that cause blindness through opaque corneal scarring. That the mechanism is keyed to inflammation may also explain why some other approaches known to reduce levels of inflammation, such as those involving mitochondrially targeted antioxidants, are effective.

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.

Heat Shock Protein Delivered as a Therapy Slows Aging in Mice

Heat shock proteins are involved in cellular quality control mechanisms that ensure correct functioning of proteins and the removal of damaged protein machinery. Research has demonstrated that more heat shock protein activity is a good thing. More quality control means less damage, and less damage means fewer secondary effects of that damage and, ultimately, a longer life. This is the way it works out in the numerous methods of modestly slowing aging in laboratory animals in which greater cellular repair and maintenance occurs as a result of the intervention. Calorie restriction is perhaps the most studied, but there are many others these days. There has been some interest in the research community in harnessing aspects of cellular quality control processes for therapeutic use, but little progress towards clinical applications. In that context, the research here is a perhaps surprisingly direct application of the principle to show benefits:

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.

Different Results from Myostatin Antibodies versus Myostatin Knockout

Reduced levels of myostatin spur greater muscle growth, and there are animal lineages and even a few individual humans with myostatin loss of function mutations. The amount of evidence and experience in the scientific community working with this genetic alteration makes it a promising compensatory therapy for age-related loss of muscle mass and strength. Indeed, trials have already been held for the use of antibodies to reduce myostatin activity, and gene therapies are a possibility for the near future once tissue coverage issues have been solved. This study quantifies some of the differences between genetic loss of myostatin and antibody therapy for suppression of myostatin. As might be expected the results are similar in character but quite different at the detailed level, showing that genetic engineering for lifelong loss of myostatin produces superior results to an adult therapy. A further comparison with gene therapy carried out in adults remains to be conducted, but the outcomes will probably fall somewhere in the middle between these two examples.

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.

Spermadine Grants Insight into a Mechanism of Age-Related Memory Dysfunction

Spermadine induces greater autophagy, the collection of cellular housekeeping processes that is associated with many of the methods demonstrated to modestly slow aging in laboratory species. Researchers here use dietary spermadine in flies to investigate one specific mechanism involved in age-related neurodegeneration. When it comes down to it, a great deal of fundamental life science research is a matter of finding or creating two similar situations and then using the small differences between them as a tool to probe the complexities of biology. Here one set of flies has a greater loss of memory, and that can be traced to specific functional changes in the synapses:

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.

A Different Approach to Reducing Mitochondrial Oxidants

Mitochondrially targeted antioxidants have been shown to modestly slow aging in a number of short-lived laboratory species, a smaller effect than that of calorie restriction. They have larger effects on inflammatory conditions, however, which is why the present thrust of clinical development is focused on a number of inflammatory eye conditions. This is in contrast to the sort of antioxidants you can buy in a supplement store, which do nothing useful, and at higher doses even appear to harm long-term health by interfering in signaling that mediates the beneficial response to exercise. Altered levels of mitochondrially generated oxidants show up in a range of methods that alter the pace of aging in animal species, mostly based on genetic engineering to alter mitochondrial operations. Here researchers are developing a drug-based approach along the same lines:

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."

An Example of the Glaring Lack of Ambition in Aging Research

The mainstream of aging research, at least in public, is characterized by a profound lack of ambition when it comes to treating aging as a medical condition. Researchers talk about slightly altering the trajectory of aging as though that is the absolute most that is possible, the summit of the mountain, and are in many cases ambivalent when it comes to advocating for even that minimal goal. It is this state of affairs that drove Aubrey de Grey and others into taking up advocacy and research, given that there are clear paths ahead to rejuvenation, not just a slight slowing of aging, but halting and reversing the causes of aging. Arguably embracing rejuvenation research programs would in addition cost less and take a much shorter span of time to produce results, since these programs are far more comprehensively mapped out than are efforts to produce drugs to alter the complex operations of metabolism so as to slightly slow the pace at which aging progresses. It is most frustrating to live in a world in which this possibility exists, yet is still a minority concern in the research community. This article is an example of the problem, in which an eminent researcher in the field takes a look at a few recently published books on aging research, and along the way reveals much about his own views on aging as an aspect of the human condition that needs little in the way of a solution. It is a terrible thing that people of this ilk are running the institutes and the funding bodies: this is a field crying out for disruption and revolution in the name of faster progress towards an end to aging.

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.

Progress Towards a Bioprinted Liver Patch for Transplantation

Tissue engineers continue to forge ahead towards the use of smaller functional sections of tissue as a way to treat failing and damaged organs. The path to the construction of entire replacement organs will be an incremental one. Organovo recently announced their intent to turn their work on bioprinted liver tissue into an option for transplantation:

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."

Theorizing on the Contribution of Gut Bacteria to Neurodegeneration

Researchers here propose a mechanism by which gut bacteria might accelerate the accumulation of misfolded proteins in the brain, known to be at the very least associated with various forms of neurodegenerative condition. Beyond mere corrleation, there is good evidence for the accumulation of aggregates of these broken proteins to be actively harmful, an important part of the disease process. The participation of gut bacteria doesn't mean we should focus on them, however; the right approach is to develop ways to safely and periodically remove these aggregates, classifying their presence as a form of damage to be repaired before it rises to harmful levels.

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."

To What Degree Does Exercise Strengthen Bones or Slow Age-Related Bone Loss?

While it is inarguable that exercise builds more and better muscle, and the outcomes are easily measured, it is much harder to determine the degree to which exercise improves bone. There is strong evidence to show that it does produce improvements to a degree that appears to taper with age, but present measurement technologies leave a lot of ambiguity and room for debate in that statement. Separately there is the question of the degree to which exercise slows the changes of aging, a related but quite different set of mechanisms. Both muscle and bone decline with age, so there is interest in the research community in exploring the biochemistry of reliable interventions, in search of ways to slow down that degeneration. This review paper is an introduction to present thinking on the effects of exercise on the quality and strength of bone tissue, and the challenges of measuring those outcomes:

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.

Bioprinting Bone Scaffolds to Guide Regrowth

The research community has made considerable progress in regenerative medicine for bone since the turn of the century, and here is an example of the way in which work on scaffolding materials merges at the edges with tissue engineering. If scaffolds can be made from the same materials as bone, they can better guide regrowth and merge into the newly formed bone tissue. The focus at the present time is on repair of injuries or bone loss due to surgery, but it will be interesting to see whether or not any of these approaches can provide value in the treatment of age-related loss of bone strength. Any method that can spur greater bone deposition is probably worthy of a second look.

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.


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