Naked mole-rats are becoming very well studied. Researchers are attempting to find the root causes of cancer immunity and exceptional longevity in this species, with an eye to creating beneficial medical biotechnologies for humans. Fight Aging! has seen a couple of items on naked mole-rats already this month, which is illustrative of the present pace:

• More on NRG-1 in Naked Mole-Rats
• Enhanced Proteasome Activity in Naked Mole Rats

Present theories are varied, but on the longevity side of the house the consensus appears to lean towards an increased resistance to forms of cellular membrane damage - naked mole rat membranes are built of a more resilient mix of proteins than those of comparable species. This is known as the membrane pacemaker hypothesis of aging:

The membrane pacemaker hypothesis predicts that long-living species will have more peroxidation-resistant membrane lipids than shorter living species. ... Resistance to oxidative damage is of particular importance in mitochondria, cellular power plants that progressive damage themselves with the reactive oxygen species they produce as a byproduct of their operation - and that gives rise to a chain of further biochemical damage that spreads throughout the body, growing ever more harmful as you age. Less damage to the mitochondria should mean slower aging, and thus more resistant mitochondrial membranes should also mean slower aging.

Continuing the naked mole-rat theme for May, here is another just-published open access paper on the resilience of naked mole-rat biology (abstract, and full article):

Studies comparing similar-sized species with disparate longevity may elucidate novel mechanisms that abrogate aging and prolong good health. We focus on the longest living rodent, the naked mole-rat. This mouse-sized mammal lives ∼8 times longer than do mice and, despite high levels of oxidative damage evident at a young age, it is not only very resistant to [cancer] but also shows minimal decline in age-associated physiological traits.

...

Like other experimental animal models of lifespan extension, naked mole-rat fibroblasts are extremely tolerant of a broad spectrum of cytotoxins including heat, heavy metals, DNA-damaging agents and xenobiotics, showing [median lethal dose] values between 2- and 20-fold greater than those of fibroblasts of shorter-lived mice. Our new data reveal that naked mole-rat fibroblasts stop proliferating even at low doses of toxin whereas those mouse fibroblasts that survive treatment rapidly re-enter the cell cycle and may proliferate with DNA damage. Naked mole-rat fibroblasts also show significantly higher constitutive levels of both p53 and Nrf2 protein levels and activity, and this increases even further in response to toxins.

...

Enhanced cell signaling via p53 and Nrf2 protects cells against proliferating with damage, augments clearance of damaged proteins and organelles and facilitates the maintenance of both genomic and protein integrity. These pathways collectively regulate a myriad of mechanisms which may contribute to the attenuated aging profile and sustained healthspan of the naked mole-rat. Understanding how these are regulated may be also integral to sustaining positive human healthspan well into old age and may elucidate novel therapeutics for delaying the onset and progression of physiological declines that characterize the aging process.

You might also look back a few years at other research into the role of Nrf2 in determining species longevity. The details can be a little overwhelming, but the big picture remains one of damage at the level of cells and protein machinery: less damage and more resilience to damage means a longer life span.

Researchers here analyze the proteome of the hypothalamus and argue for an important role in coordinating bodily responses to ongoing changes caused by aging: "The aging process affects every tissue in the body and represents one of the most complicated and highly integrated inevitable physiological entities. The maintenance of good health during the aging process likely relies upon the coherent regulation of hormonal and neuronal communication between the central nervous system and the periphery. Evidence has demonstrated that the optimal regulation of energy usage in both these systems facilitates healthy aging. However, the proteomic effects of aging in regions of the brain vital for integrating energy balance and neuronal activity are not well understood. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity. Therefore, a greater understanding of the effects of aging in the hypothalamus may reveal important aspects of overall organismal aging and may potentially reveal the most crucial protein factors supporting this vital signaling integration. In this study, we examined alterations in protein expression in the hypothalami of young, middle-aged, and old rats. ... Based upon our rigorous analyses, we show that endogenous physiological responses to aging may be strongly orchestrated by the expression level of the GIT2 protein. The relevance of the hypothalamic expression level of this protein to the aging process in both neuronal and energy-controlling tissues reinforces the importance of this organ in the potential future development of targeted pharmacotherapeutics designed to interdict a multitude of age-related disorders."

Link: http://dx.doi.org/10.1371/journal.pone.0036975

A possible method of boosting muscle repair, and thus treating muscle wasting conditions - such as the sarcopenia that attends aging: "a lipid signaling molecule called sphingosine-1-phosphate or 'S1P' can trigger an inflammatory response that stimulates the muscle stem cells to proliferate and assist in muscle repair. ... mdx mice, which have a disease similar to Duchenne Muscular Dystrophy, exhibit a deficiency of S1P, [and] boosting their S1P levels improves muscle regeneration ... The ability of muscles to regenerate themselves is attributed to the presence of a form of adult stem cells called 'satellite cells' that are essential for muscle repair. Normally, satellite cells lie quietly at the periphery of the muscle fiber and do not grow, move or become activated. However, after muscle injury, these stem cells 'wake up' through unclear mechanisms and fuse with the injured muscle, stimulating a complicated process that results in the rebuilding of a healthy muscle fiber. S1P is a lipid signaling molecule that controls the movement and proliferation of many human cell types. ... S1P is able to 'wake up' the stem cells at the time of injury. It involves the ability of S1P to activate S1P receptor 2, one of its five cell surface receptors, leading to downstream activation of an inflammatory pathway controlled by a transcription factor called STAT3. [This results] in changes in gene expression that cause the satellite cell to leave its 'sleeping' state and start to proliferate and assist in muscle repair. ... If these findings are also found to be true in humans with Duchenne Muscular Dystrophy, it may be possible to use similar approaches to boost S1P levels in order to improve satellite cell function and muscle regeneration in patients with the disease. Drugs that block S1P metabolism and boost S1P levels are now being tested for the treatment of other human diseases including rheumatoid arthritis. If these studies prove to be relevant in Duchenne patients, it may be possible to use the same drugs to improve muscle regeneration in these patients. Alternatively, new agents that can specifically activate S1P receptor 2 could also be beneficial in recruiting satellite cells and improving muscle regeneration in muscular dystrophy and potentially other diseases of muscle."

Link: http://www.sciencedaily.com/releases/2012/05/120515070307.htm

You might recall that late last year I pointed out a large Japanese longitudinal study on incidental moderate exercise and lifetime medical costs:

The authors followed up 27,738 participants aged 40-79 years and prospectively collected data on their medical expenditure and survival covering a 13-year-period. ... The present results indicate that the multiadjusted lifetime medical expenditure from the age of 40 years for those who walked ≥1 h per day was significantly lower by 7.6% in men and non-significantly lower by 2.7% in women than for those who walked <1 h per day. This decrease in lifetime medical expenditure was observed in spite of a longer life expectancy (1.38 years for men and 1.16 years for women) among those who walked ≥1 h per day.

In another, more open access recent paper, the same authors have crunched the numbers for variations in weight among study participants. The story is much the same, as one would expect:

Although four previous studies have examined the association between obesity and lifetime medical expenditure, the results were inconsistent. ... We therefore conducted a 13-year prospective observation of 41,965 Japanese adults aged 40-79 years living in the community, which accrued 392,860 person-years. We examined the association between BMI and lifetime medical expenditure, based on individual medical expenditure and life table analysis. We collected data for survival and all medical care utilisation and costs, excluding home care services provided home health aides, nursing home care and preventive health services in participants of this cohort study.

...

In spite of their short life expectancy, obese men and women had approximately 14.7% and 21.6% higher lifetime medical expenditure in comparison with normal weight participants, respectively.

Don't get fat, don't stay fat, and don't be a couch potato. Thus speaks the weight of evidence - but then we all knew that, right? Being unhealthy has definitive material costs in the long term: years of life shaved off, the rot of your body and mind, and the monetary cost of medical services you would otherwise not have needed. There are plenty of people in this world, far too many, who don't presently have the luxury of choice when it comes to being healthy: the genetically impaired, the immune-damaged, the infected, the wounded. Why fritter away your choice for the sake of eating and laziness? It is almost a gesture of contempt.

The media and public at large have been trained to think of medicine, and especially longevity-related medicine, in terms of pills - things you can consume, colorful drug capsules produced in the old-style fashion by Big Pharma. This is somewhat ridiculous, and leads to a focus on the entirely the wrong branches of research, those unlikely to deliver meaningful healthy life extension. The future of rejuvenation biotechnology involves gene therapies, infusions of bacterial enzymes, and so forth; for the foreseeable future little of that will be stuff that you stick into your mouth. Calling these medicines drugs rather than procedures cheapens the complexity of what is being designed and developed. Nonetheless, the oral fixation in regard to public perceptions of medicine continues, fed by the lazy press and the self-interested supplement industry. Here is an example of that sort of headlining: "But imagine if there were a drug that would slow down the aging process itself, a drug that didn't just treat a single disease but instead targeted multiple diseases of old age at once? It may sound far-fetched, but that's precisely what longevity scientists are working hard to produce. ... It's not just that we're trying to make people live longer; we're trying to make people live healthier. This is an exciting time for research. ... Indeed, top-notch research labs are rolling out studies at a rapid rate, and a growing chorus of experts believe the advances being made will ultimately lead to a crop of drugs capable of extending healthy lifespans. Signs of progress are abundant in medical journals. ... [researchers] published results showing they could markedly delay the onset of age-related diseases in mice by killing off the rodents' senescent cells. Senescent cells have stopped dividing and accumulate as organisms age. Though seemingly dormant, they're not: Just as old cars in junkyards can leak oil for years, they emit harmful substances that appear to fuel many of the diseases that strike older people. ... And it's not just senescence research that is stoking excitement. Another team of scientists [has] managed to control the aging process by targeting specialized structures at the tips of chromosomes called telomeres. ... Other scientists have found that feeding aging mice rapamycin - an immunosuppressant that's used to prevent organ rejection after transplants - can extend the lifespan of mice significantly."

Link: http://health.usnews.com/health-news/articles/2012/05/14/the-hunt-for-an-anti-aging-pill-is-on

Calorie restriction extends healthy life span, and that seems to largely work through the level of methionine in the diet, though minimizing visceral fat tissue looks to be an important effect as well: "It is known that a global decrease in food ingestion (dietary restriction, DR) lowers mitochondrial ROS generation (mitROS) and oxidative stress in young immature rats. This seems to be caused by the decreased methionine ingestion of DR animals. This is interesting since isocaloric methionine restriction in the diet (MetR) also increases, like DR, rodent maximum longevity. However, it is not known if old rats maintain the capacity to lower mitROS generation and oxidative stress in response to MetR similarly to young immature animals, and whether MetR implemented at old age can reverse aging-related variations in oxidative stress. In this investigation the effects of aging and 7 weeks of MetR were investigated in liver mitochondria of Wistar rats. MetR implemented at old age decreased mitROS generation, percent free radical leak at the respiratory chain and mtDNA oxidative damage without changing oxygen consumption. Protein oxidation, lipoxidation and glycoxidation increased with age, and MetR in old rats partially or totally reversed these age-related increases. ... In conclusion, treating old rats with isocaloric short-term MetR lowers mitROS production and free radical leak and oxidative damage to mtDNA, and reverses aging-related increases in protein modification. Aged rats maintain the capacity to lower mitochondrial ROS generation and oxidative stress in response to a short-term exposure to restriction of a single dietary substance: methionine."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22580750

A few years ago, a Spanish research team created transgenic mice that lived significantly longer than normal by combining increased p53 with increased telomerase. p53 is a cancer suppressor that under usual circumstances reduces the ability of stem cells to replace worn cells in aging tissue - less cell proliferation means a lower chance of cancer over time, but also faster aging as the tissues of the body wear and fail more readily. More telomerase, on the other hand, achieves the opposite end: dynamic, longer lasting cells that also produce way more cancers in the course of their more energetic operations. This, in any case, is the consensus view of how these elements work in the biochemistry of mammals:

The standard reading is that the "Super p53" mice are getting less cancer, but are having their [life spans] restrained by lack of tissue replenishment due to stem cell loss, while the telomerase transgenics are on the opposite horn of the same dilemma. It seems at least possible that if one overlaid the strong cancer resistance conferred by the former, with the increase in stem cell mobilization and proliferative capacity of the latter, you'd wind up with a long-lived, slow-aging mouse.

I should note in passing that it is possible through clever techniques to have enhanced p53 provide both a cancer and longevity benefit in and of itself. But in the case of the Spanish research team, their work is more simply a case of balancing one mixed benefit with the opposite mixed benefit - and coming out ahead of the game. The researchers recently published results for the next stage of their research program: taking the modifications that had been transgenic to date and instead applying them as gene therapies to adult mice. This is a step on the road to building some form of beneficial medical technology for humans:

CNIO scientists successfully test the first gene therapy against aging-associated decline:

Mice treated at the age of one lived longer by 24% on average, and those treated at the age of two, by 13%. The therapy, furthermore, produced an appreciable improvement in the animals' health, delaying the onset of age-related diseases - like osteoporosis and insulin resistance - and achieving improved readings on ageing indicators like neuromuscular coordination.

The gene therapy utilised consisted of treating the animals with a DNA-modified virus, the viral genes having been replaced by those of the telomerase enzyme, with a key role in ageing. Telomerase repairs the extremes of chromosomes, known as telomeres, and in doing so slows the cell's and therefore the body's biological clock. When the animal is infected, the virus acts as a vehicle depositing the telomerase gene in the cells.

...

In 2007, Blasco's group proved that it was feasible to prolong the lives of transgenic mice, whose genome had been permanently altered at the embryonic stage, by causing their cells to express telomerase and, also, extra copies of cancer-resistant genes. These animals live 40% longer than is normal and do not develop cancer. The mice subjected to the gene therapy now under test are likewise free of cancer. Researchers believe this is because the therapy begins when the animals are adult so do not have time to accumulate sufficient number of aberrant divisions for tumours to appear.

...

As Blasco says, "ageing is not currently regarded as a disease, but researchers tend increasingly to view it as the common origin of conditions like insulin resistance or cardiovascular disease, whose incidence rises with age. In treating cell ageing, we could prevent these diseases".

You'll have to wait for the paper to show up at the EMBO Molecular Medicine website to get more details on the lifespan data, degree to which cancer is removed from the picture, and what type of mouse is being used here - e.g. are they using the transgenic enhanced p53 mouse as a baseline? That shouldn't take too long, and it is an open access publication so we'll all have a chance to read the details.

As an aside, aging defined as a disease is a topic that crops up frequently - but only because of the structure of medical regulation. Regulators in the US, for example, will only approve medical technologies for named, defined diseases. Aging is not on their list, but the problem is not that fact, but rather that a list of what is permitted and an organization to enforce it even exists in the first place.

The employees and appointees of the US Food and Drug Administration have caused an incredible destruction of value and progress over the time that the agency has existed. Their regulatory policies become ever more onerous with each passing year, as unaccountable bureaucrats follow their incentives: nothing good can happen to their careers as a result of approving new technologies, and nothing bad tends to happen to their careers as a result of making it really, really hard to bring new medicine to the clinic. So of course you wind up with an organization whose members collectively pay nothing more than lip service to their declared mission, while working to make sure that medicine stays moribund in a slow-motion stasis.

Bone morphogenetic protein 2 (BMP-2) has been used to spur healing in regenerative medicine research in past years. Here researchers are investigating its use in bone regrowth: scientists are "concentrating on the creation of new bone tissue with the aid of a biomolecule called BMP-2, which is a protein that makes bones grow. The problem with BMP-2 is that it breaks down in the body in just a few minutes. ... What's new, and what I show in my dissertation, is that by having a gel-like substance carry the protein, a so-called hydrogel, you can control both how and where the new bone is to grow ... This hydrogel can be injected and is moreover made from a type of sugar (hyaluronic acid). It occurs naturally in the body in humans and animals and is otherwise used in cosmetic products for treating wrinkles. This offers major advantages. ... On the one hand, you avoid open surgery and the risk of complications and infections that entails, and, on the other hand, there is no risk that the body will reject it. ... Applications in healthcare include both healing complicated bone fractures and growing bone tissue where there is too little or none at all. This involves defects following bone fractures and cancer or when the jawbone is too weak to support a tooth implant. Clinical testing is already underway. ... The tests show that it's working well, but the problem we need to solve is how to determine the optimal dosage of the protein. Otherwise inflammations can occur in surrounding tissue."

Link: http://medicalxpress.com/news/2012-05-smart-material-bone.html

Researches make an incremental step forward in understanding the root causes of rheumatoid arthritis: "Untangling the root cause of rheumatoid arthritis has been a difficult task for immunologists, as decades of research has pointed to multiple culprits in our immune system, with contradictory lines of evidence. Now, [researchers] announce that it takes a diverse array of regulatory T cells (a specialized subset of white blood cells) to prevent the immune system from generating the tissue-specific inflammation that is a hallmark of the disease. Regulatory T cell diversity, the researchers say, provides a cumulative protective effect against rheumatoid arthritis. ... regulatory T cells (or Tregs) are a necessary component to either restrain (or encourage) the immune system's inflammatory response. Tregs are activated as molecules on their surface membranes called T cell receptors interact with 'friendly' or 'self' molecules - a way for the immune system to recognize friend from foe. Mismanagement of these Tregs, which normally serve to restrain the immune system from over-reacting to healthy tissue, could then lead to runaway inflammation. In this study, the researchers sought to examine how T cell receptors affect the ability of Tregs to suppress arthritis in a mouse that had been bred to express a 'self' molecule that drives arthritis. They showed that an array of Tregs given to the mice effectively stops arthritis. Unexpectedly, however, Tregs that are specific for the surrogate 'self' molecule do not prevent arthritis. ... We find that [a] diverse repertoire of Tregs are very effective. All of these Tregs, together, influence other components of the immune system which serves to slow down the inflammatory process that causes RA."

Link: http://www.sciencedaily.com/releases/2012/05/120508142626.htm

Metformin is a drug that shows up in discussion here every so often. It is thought to be a calorie restriction mimetic, recapitulating some of the metabolic changes caused by the practice of calorie restriction. Its effects on life span in laboratory animals are up for debate and further accumulation of evidence - the results are on balance more promising than the generally dismal situation for resveratrol, but far less evidently beneficial than rapamycin. Like rapamycin, metformin isn't something you'd want to take as though it were candy, even if the regulators stood back to make that possible, as the side effects are not pleasant and potentially serious.

I should note as an aside that while ongoing research into the effects of old-school drugs of this nature is certainly interesting, it doesn't really present a path to significantly enhanced health and longevity. It is a pity that such research continues to receive the lion's share of funding, given that the best case outcome is an increase in our knowledge of human metabolism, not meaningful longevity therapies. Even if the completely beneficial mechanism of action is split out from the drug's actions - as seems to be underway for rapamycin - the end results will still only be a very modest slowing of aging. You could do better by exercising, or practicing calorie restriction.

For the billions in funding poured into these drug investigation programs, there should be a better grail at the end of the road - such as that offered by the SENS vision of rejuvenation biotechnology. Targeted repair of the biological damage of aging is a far, far better strategy than gently slowing the pace of damage accumulation through old-style drug discovery programs. This is a biotechnology revolution: time to start acting like it.

Anyway, aside done, let me point you to a recent open access review on metformin: the interesting work that won't really be in any way relevant to the future of your longevity, but which I'll wager has raised more funding as an object of study than the entire present extant SENS program and directly related scientific studies:

Metformin, an oral anti-diabetic drug, is being considered increasingly for treatment and prevention of cancer, obesity as well as for the extension of healthy lifespan. Gradually accumulating discrepancies about its effect on cancer and obesity can be explained by the shortage of randomized clinical trials, differences between control groups (reference points), gender- and age-associated effects and pharmacogenetic factors. Studies of the potential antiaging effects of antidiabetic biguanides, such as metformin, are still experimental for obvious reasons and their results are currently ambiguous.

...

The wave of interest, with periodical decays and increasing surges, was associated with the attempts to use antidiabetic biguanides [such as metformin] to control body weight and tumor growth. Another facet of the situation is that almost 45 years ago these drugs were suggested to promote longevity. Over the last years, the expanding bodies of relevant evidence, which mainly related to metformin, started to merge and occupy increasing place in current literature. The objective of the present essay is to attract more attention to accumulating inconsistencies. The first two sections of the essay, which are related to obesity and cancer, are based mostly on clinical data. The third section, which is related to aging or, rather, antiaging, is based predominately on experimental evidence obtained in rodents. Clearly, obesity and cancer have numerous interrelationships with aging, [however], we will separate these aspects for the sake of clarity in discussing the relevant effects of metformin.

See what you think; it makes for an interesting read - and includes a table of results from a number of life span studies that are, indeed, all over the map. It somewhat reinforces the point that unambiguous success in extending healthy life is not going to arrive from this quarter. Think SENS, not drug discovery - what will come from the drug discovery clade is a slow, grinding, and expensive cataloging of the fine details of genetics, metabolism, and aging in mammals.

In recent years resveratrol has clearly fallen below the dividing line for work that is useful from a longevity perspective - if it could extend life significantly in mice, that would have been demonstrated by now. You might compare with the size of the effects on mouse lifespan for rapamycin to provide an example of a compound that is worth investigating. There is, however, a lot of money sunk into work on resveratrol and the underlying mechanisms of sirtuins, so don't expect that to halt any time soon. Research and developer institutions are prone to inertia, just like all other fields of human endeavor. In any case, here is some of the latest work on SIRT1: "If resveratrol needs SIRT1 to improve health, then animals lacking the gene should not get any benefits from the chemical. His lab published that experiment in yeast in 2003. But mice lacking SIRT1 die in the womb, or they are born with developmental defects such as blindness. To get around that problem, [researchers] engineered 'conditional knockout' mice whereby SIRT1 can be inactivated in adulthood. ... It took us two weeks to do the experiment in yeast, and five years in mouse, but finally we're there ... In normal mice, resveratrol combated the effects of a high-fat diet by boosting the efficiency of energy-generating organelles called mitochondria in skeletal muscle tissue. This effect vanished in adult mice without a working version of SIRT1. Yet SIRT1 wasn't responsible for all the beneficial effects of resveratrol ... Resveratrol stabilized the blood glucose levels of both normal and SIRT1-lacking mice on fatty diets. The chemical also improved liver health in mice without SIRT1. [The researchers also contend] that a lot the confusion over how resveratrol works comes down to dosage. At very high doses it binds other proteins besides SIRT1 ... For instance, a signalling protein called AMPK is also important to resveratrol's beneficial effects on metabolism. ... low doses of resveratrol boosted AMPK levels in various cells that expressed SIRT1, but not cells without the sirtuin. Much higher doses of resveratrol, however, activated AMPK irrespective of whether the cells expressed SIRT1."

Link: http://blogs.nature.com/news/2012/05/row-over-resveratrol-rumbles-on.html

Singularity Hub looks at the tissue engineering of teeth: "For years, researchers have investigated stem cells in an effort to grow teeth made for a person's own cells. Toward this end, [scientists] have developed methods to control adult stem cell growth toward generating dental tissue and 'real' replacement teeth. [The] researchers' approach is to extract stem cells from oral tissue, such as inside a tooth itself, or from bone marrow. After being harvested, the cells are mounted to a polymer scaffold in the shape of the desired tooth. The polymer is the same material used in bioreabsorable sutures, so the scaffold eventually dissolves away. Teeth can be grown separately then inserted into a patient's mouth or the stem cells can be grown within the mouth reaching a full-sized tooth within a few months. So far, teeth have been regenerated in mice and monkeys, and clinical trials with humans are underway, but whether the technology can generate teeth that are nourished by the blood and have full sensations remains to be seen. Teeth present a unique challenge for researchers because the stem cells must be stimulated to grow the right balance of hard tissue, dentin and enamel, while producing the correct size and shape."

Link: http://singularityhub.com/2012/05/10/toothless-no-more-researchers-using-stem-cells-to-grow-new-teeth/

For some years researchers have been investigating the mechanisms of limb and organ regrowth in lower animals like salamanders, with an eye to finding out how easy or hard it would be to recreate those same capabilities in mammals - such as we humans. Do we retain the core mechanisms, lying dormant in our biochemistry, or have they been completely lost? Time and ongoing research will tell.

But these are not the only areas of regrowth wherein researchers might learn something of interest to regenerative medicine. Consider that elk regularly regrow their antlers, for example - not a simple organ by any means. Further down the scale of impressiveness, we might consider the many higher animals that regularly regrow feathers or coats of hair. Is there anything in their biochemistry that might be discovered and adapted to cause humans to regenerate in situations where they normally do not?

If you buy into the argument that salamander biochemistry is worth investigation, then it's hard to reject similar investigations in other species capable of the lesser forms of regrowth mentioned above. An open access paper is presently doing the rounds on this topic; you can read the summary in the release, or look at the paper itself:

Physiological Regeneration of Skin Appendages and Implications for Regenerative Medicine

The concept of regenerative medicine is relatively new, but animals are well known to remake their hair and feathers regularly by normal regenerative physiological processes. Here, we focus on 1) how extrafollicular environments can regulate hair and feather stem cell activities and 2) how different configurations of stem cells can shape organ forms in different body regions to fulfill changing physiological needs.

Regenerative medicine has great potential. The main challenge is how to elicit and harness the power of regeneration. Currently, the major issues are how to obtain stem cells, how to pattern stem cells into organized tissues and organs, and how to deliver stem cell products to patients. Although human beings have very limited powers of regeneration, many animals have robust regenerative powers, distilled and selected over millions of years of evolution. Here, we review fundamental principles of regenerative biology learned from nature in the hope that they can be applied to help the progress of regenerative medicine.

...

Using the episodic regeneration of skin appendages as a clear readout, we have the opportunity to understand and modulate the behavior of adult stem cells and organ regeneration at a level heretofore unknown. Through this work, we hope to be able to establish or improve the stem cell environment so it can be applied to regenerative medicine.

In conclusion, we think it will be very productive to learn how nature manages the physiological regeneration process. This is a reprogramming process in which the genetic and epigenetic events converge to generate complex functional forms, depending on the physiological need in different parts of the body and at different stages of life. Principles learned from regenerative biology can then be applied toward regenerative medicine.

An article from the Wellcome Trust: "Researchers have been engineering cartilage in the laboratory for 15 years or more, but as yet the tissues they have created don't function properly in human joints. [Researchers] are taking a new approach to try to bridge the gap between laboratory-created cartilage and the tissue our bodies make. ... Biological texts show that these lab-grown tissues have the appearance, texture, and protein and mineral components of bone and cartilage. But once they are tested in an animal, these tissues simply don't behave quite like the natural tissues they are supposed to replicate. ... Joints are remarkable feats of engineering, but efforts to grow them in the lab have focused mostly on their biology. ... Biologists attempting to create cartilage and bone over the past 15 years have typically tested the mechanical properties of their laboratory-grown tissue - for example, whether it is rubbery and resilient enough when pressure is applied. ... Just because biological tests indicate a tissue looks like bone and feels like bone, doesn't actually mean it is bone ... This is where an engineering perspective becomes important. To look at how close a match these laboratory-generated tissues really are to native bone and cartilage, [researchers] supplemented the biological analyses with engineering tests, such as bio-Raman microspectroscopy. ... You shine a laser on the material, and the way the light scatters gives you an idea of the bonds between its components. Different mineral types form different bonds, so you get a much more precise picture of what is actually present. ... If a lab-grown tissue seems from some tests to be the real thing but isn't really, then it won't behave like it once it has been implanted in a human body. ... [The researchers aim] to use an engineering approach to create a whole osteochondral interface in which bone and cartilage transition seamlessly into each other like they do in the body. ... That's the only way it will effectively transmit loads to the underlying bone. And because bone will heal, it will heal the construct into the joint."

Link: http://www.wellcome.ac.uk/News/2012/Features/WTVM054966.htm

Following on from a recent post on the involution of the thymus in adults, the process by which it ceases to generate immune cells and atrophies, here is a another paper that considers some of the possible paths to interventions that maintain the thymus into old age. Given experiments in mice showing that transplant of a young thymus extends life, this seems worthy of further investigation: "The thymus is the primary organ for T-cell differentiation and maturation. Unlike other major organs, the thymus is highly dynamic, capable of undergoing multiple rounds of almost complete atrophy followed by rapid restoration. The process of thymic atrophy, or involution, results in decreased thymopoiesis and emigration of naïve T cells to the periphery. Multiple processes can trigger transient thymic involution, including bacterial and viral infection(s), aging, pregnancy and stress. Intense investigations into the mechanisms that underlie thymic involution have revealed diverse cellular and molecular mediators, with elaborate control mechanisms. This review outlines the disparate pathways through which involution can be mediated, from the transient infection-mediated pathway, tightly controlled by microRNA, to the chronic changes that occur through aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22539280