It seems that this is a week for announcing significant progress in tissue engineering. You might recall that one of the groups involved in recellularization research transplanted a trachea into a human recipient a couple of years ago. The organ was from a donor, stripped of all its cells, and the remaining natural scaffold of the extracellular matrix repopulated with cells from the recipient. The end result was a transplanted organ that would not be rejected by the immune system. The same researchers have now gone one step further and successfully transplanted an entirely synthetic trachea grown from the patient's cells on an artificial scaffold - no donor organ required.

Surgeons have performed the first transplant operation using an organ wholly grown in a laboratory to give a man a new windpipe. The 36-year-old is recovering after surgeons implanted the world's first wholly lab-grown organ into his body.

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Professor Paolo Macchiarini, a Spanish expert in regenerative medicine who led the groundbreaking operation, designed the Y-shaped synthetic trachea scaffold with Professor Alexander Seifalian, from University College London. The Y-shaped structure was made from a plastic-like "nanocomposite" polymer material consisting of microscopic building blocks. Two days after stem cells were placed into the scaffold they had grown into tracheal cells ready for transplantation. Since the organ was built from cells originating from the patient, there was no risk of it being rejected by his immune system.

In conjunction with lines of research like organ printing, this pace of work bodes well for the 2030s as a time in which failing or badly injured organs are no longer automatically fatal or the cause of lifelong disability for the young. There is still the question of how best to take advantage of this for the old, however: the frailty that comes with aging brings with it a much lower survival rate and success rate for major surgery - and any significant transplant is major surgery. Regrowth of organs alone is not the way to greatly extend the maximum human lifespan on a timescale that matters. Other technologies are needed as well:

There are many whole-body, multi-organ, or regional biochemical feedback and control loops in the body. There are types of age-related damage that involve the intracellular accumulation of biochemical junk - simply replacing cells doesn't get rid of that. If your only tool is bioprinting (which won't be the case, but let us think inside the box for a while here), then the solution to these problems starts to look like replacing more of the body at one time.

You can't just replace the brain, of course, which remains an important limiting factor and the real driving need for in situ repair technologies that operate at the level of cells, buildup of protein aggregates, and broken cellular machinery.

The quality of the immune system in later years has a strong impact on mortality rates and frailty - and that quality varies with different genetic profiles. Thus it follows that among the genetic variants known to affect human longevity, some are involved with the immune system: "The ageing process is very complex. Human longevity is a multifactorial trait which is determined by genetic and environmental factors. Twin and family studies imply that up to 25% of human lifespan is heritable. The longevity gene candidates have generally fallen into the following categories: inflammatory and immune-related factors, stress response elements, mediators of glucose and lipid metabolism, components of DNA repair and cellular proliferation and mitochondrial DNA haplogroups. Because of the central role of HLA molecules in the development of protective immunity and the extraordinary degree of polymorphism of HLA genes, many studies have addressed the possible impact of these genes on human longevity. Most of the data available so far demonstrated a possible role of HLA class II specificities in human longevity but definitive evidence has remained elusive. Although the data are limited and controversial, it has been hypothesized that longevity could be associated with cytokine gene polymorphisms correlating with different levels of cytokine production, thereby modulating immune responses in health and disease. Because of the essential role of cytokines in immune responses, the regulation of cytokine gene expression and their polymorphic nature, the genetic variations of these loci with functional significance could be appropriate immunogenetic candidate markers implicated in the mechanism of successful ageing and longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21726414

Some work here on IFG-1, not to be confused with IGF-1, which is also of interest in longevity: "When researchers at the Buck Institute dialed back activity of a specific mRNA translation factor in adult nematode worms they saw an unexpected genome-wide response that effectively increased activity in specific stress response genes that could help explain why the worms lived 40 percent longer under this condition. ... Scientists have identified a number of so-called 'longevity' genes active in many species. However, the mechanisms by which those genes impact lifespan remain poorly understood. ... the majority of research involving those genes has focused on transcription, the first level of cellular activity whereby DNA produces RNA. This research focuses on translation, whereby RNA specifies the production of proteins. ... [Researchers] inhibited expression of the mRNA translation factor, IFG-1, in adult worms. IFG-1 is important for growth and development ... "Turning down ifg-1 expression flips a switch that turned down growth and reproduction, but increased their healthspan as well as their lifespan. ... Our primary interest is to understand the biological basis of aging. This will help identify molecular targets that can be used to develop therapeutics that would slow age-related diseases and extend the healthy years of life."

Link: http://www.sciencedaily.com/releases/2011/07/110705123340.htm

Publicity materials for a good-looking incremental advance from the tissue engineering community are doing the rounds in the press at the moment.

Researchers at The Saban Research Institute of Children's Hospital Los Angeles have successfully created a tissue-engineered small intestine in mice that replicates the intestinal structures of natural intestine - a necessary first step toward someday applying this regenerative medicine technique to humans.

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Working in the laboratory, the research team took samples of intestinal tissue from mice. This tissue was comprised of the layers of the various cells that make up the intestine - including muscle cells and the cells that line the inside, known as epithelial cells. The investigators then transplanted that mixture of cells within the abdomen on biodegradable polymers or "scaffolding."

What the team wanted to happen did - new, engineered small intestines grew and had all of the cell types found in native intestine. Because the transplanted cells had carried a green label, the scientists could identify which cells had been provided - and all of the major components of the tissue-engineered intestine derived from the implanted cells. Critically, the new organs contained the most essential components of the originals.

The original paper is also available, for those who are interested. The normal caveats apply here - it's a promising advance for researchers to show that they can make lengths of intestine grow correctly inside a living mouse, using scaffolds seeded with cells. But bear in mind that this is only a demonstration: the new section of intestine isn't hooked up or being put under load. It'll be a few more years, I'd guess, before we see mice (or perhaps pigs) with tissue engineered and functional replacement small intestines.

If you'd like to learn more, I noticed an educational set of pages on the topic put up by the students at UCI:

In tissue engineering, there are two fundamentally different approaches that can be taken. The first is to replicate the organanatomically, with the expectation that the function of the engineered organ will therefore be the same. The second approach is simply to replicate its function. Researchers who aim to engineer intestine have adopted the anatomical approach with the key problems including the development of a muscular layer and neuronal innovation are major challenges to its success. On the other hand,if the aim is to develop an absorptive surface with neointestinal epithelium, it is possible to be more imaginative about how this can be achieved.

A confirming review of studies: "Telomeres play a key role in the maintenance of chromosome integrity and stability, and telomere shortening is involved in initiation and progression of malignancies. A series of epidemiological studies have examined the association between shortened telomeres and risk of cancers, but the findings remain conflicting. ... A dataset composed of 11,255 cases and 13,101 controls from 21 publications was included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and the relative telomere length. ... The results showed that shorter telomeres were significantly associated with cancer risk compared with longer telomeres. ... Studies have showed that telomeres are critical for maintaining genomic integrity and that telomere dysfunction or shortening is an early, common genetic alteration acquired in the multistep process of malignant transformation. In addition, telomere dysfunction has been found to be associated with decreased DNA repair capacity and complex [cellular] abnormalities. Both of animal studies and clinical observations have shown that shorter telomeres were associated with increased risk of cancers, such as epithelial cancers. However, telomere shortening might play conflicting roles in cancer development. For example, the progressive loss of telomeric repeats with each cell division can induce replicative senescence and limit the proliferative potential of a cell, thus functioning as a tumor suppressor. But, once telomeres reach a critical length, it will result in chromosome break, causing genome instability and enhancing potential for malignant transformation."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3112149/

Altering cells used in tissue engineering so as to obtain a better result is a very viable prospect, as demonstrated in a recent investigation of tendon regeneration: "The basic function of tendon is to transmit force from muscle to bone, which makes limb and joint movement possible. Therefore tendons must be capable of resisting high tensile forces with limited elongation. ... the mechanical properties of tendons are related to the fibril diameter distribution, large fibrils could withstand higher tensile forces. ... In the healing tendon, a uniform distribution of small diameter collagen fibrils has been found with poorer mechanical properties than native tissue and shows no improvement of mechanical properties with time ... The present study for the first time demonstrated the use of a scaffold-free tissue engineered tendon model for investigating the biological function of collagen V in tendon fibrillogenesis. ... Conclusively, it was demonstrated that Col V siRNA engineered tenocytes improved tendon tissue regeneration. ... These findings present a good example of in vitro tissue engineering model for tendon biology investigation and may provide basis for future development of cell or gene therapy for tendon repair."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119690/

Prioritizing the few exceptionally long-lived mammal species for full genome sequencing has been a few years in the making as a project, but I see that the researchers who initiated that effort have now completed the first item on their list:

Naked mole rat's genome 'blueprint' revealed

The industrious but unlovely naked mole rat is the latest creature to have its genome sequenced by scientists. A genetic blueprint for this bizarre-looking rodent could help researchers understand why it is so long-lived.

Scientists sequence DNA of cancer-resistant rodent

For the first time, scientists have sequenced the genome of the naked mole-rat to understand its longevity and resistance to diseases of ageing. Researchers will use the genomic information to study the mechanisms thought to protect against the causes of ageing, such as DNA repair and genes associated with these processes. To date, cancer has not been detected in the naked mole-rat. Recent studies have suggested that its cells possess anti-tumour capabilities that are not present in other rodents or in humans. Researchers at Liverpool are analysing the genomic data and making it available to researchers in health sciences, providing information that could be relevant to studies in human ageing and cancer.

Dr Joao Pedro Magalhaes, from the University of Liverpool's Institute of Integrative Biology, said: "The naked mole-rat has fascinated scientists for many years, but it wasn't until a few years ago that we discovered that it could live for such a long period of time. It is not much bigger than a mouse, which normally lives up to four years, and yet this particular underground rodent lives for three decades in good health. It is an interesting example of how much we still have to learn about the mechanisms of ageing. We aim to use the naked mole-rat genome to understand the level of resistance it has to disease, particularly cancer, as this might give us more clues as to why some animals and humans are more prone to disease than others. With this work, we want to establish the naked mole-rat as the first model of resistance to chronic diseases of ageing."

It will likely take a few years for the first interesting results to emerge from the genomic data - grants must be written, teams formed, studies carried out. Science, while fast, isn't yet instant. While researchers have a good idea as where in naked mole rat biochemistry they should be looking for both cancer resistance and longevity, molecular biology is an inordinately complex field of study. On the longevity side of the house, the composition of cellular membranes appears to be of greatest interest. You might look back into the Fight Aging! archives at these posts:

• Built Differently, Down in the Membranes
• Comparative Biology and the Membrane Pacemaker Hypothesis

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.