The evidence points toward mitochondrial structure and function being very important in the progression of aging within a species and differences in life span between species. Here researchers review some of the mechanisms involved: "Mitochondria are considered major regulators of longevity, although their exact role in aging is not fully understood. Data from different laboratories show a negative correlation between reactive oxygen species (ROS) generated by complex I and lifespan. This suggests that complex I has a central role in the regulation of longevity. Here, we review data that both support and refute the role of complex I as a pacemaker of aging. We include data from our laboratory, where we have manipulated ROS production by the electron transport chain (ETC) in Drosophila melanogaster. The by-pass of complex I increases the lifespan of the fruit fly, but it is not clear if this is caused by a reduction in ROS or by a change in the NAD+ to NADH ratio. We propose that complex I regulates aging through at least two mechanisms: (1) an ROS-dependent mechanism that leads to mitochondrial DNA damage and (2) an ROS-independent mechanism through the control of the NAD+ to NADH ratio. Control of the relative levels of NAD+ and NADH would allow the regulation of (1) glyco- and (2) lipoxidative-damage and (3) the activation of sirtuins." Amongst other things, the NAD+ / NADH ratio determines how much in the way of damaging free radicals a cell exports into the surrounding environment.

Link: http://www.ncbi.nlm.nih.gov/pubmed/21471732

The process of understanding how to manipulate stem cells goes hand in hand with being able to coax them into forming more complex structures, recapitulating the path taken during the original development of the body when young. The state of the art at the present time is crude in comparison to what takes place in our bodies: the only way that researchers can presently obtain complex tissues is by using the extracellular matrix extracted from donor tissue as a guide for new growth. That guidance is as much chemical as structural, which is illustrated in the following recently announced research.

'Retina in a Dish' is the Most Complex Tissue Ever Engineered in the Lab:

Researchers in Japan have grown a retina from mouse embryonic stem cells in a lab, but this isn't just another incremental advance in tissue engineering. Scientists claim their "retina in a dish" is by no small degree the most complex biological tissue yet engineered.

If the breakthrough can be adapted to work with human cells, it could provide a retina that is safe for transplantation into human eyes, providing a potential cure for many kinds of blindness. That's still years away, but in the meantime the lab-grown mouse tissue could provide researchers with a wealth of information on eye diseases and potential treatments for them.

Cultured mouse embryonic stem cells self-organize into a complex retinal structure:

Starting with the culture conditions they had established for retinal differentiation, the researchers added matrix proteins that they hoped would encourage the formation of the more rigid retinal epithelial structures. They then seeded the culture with mouse [embryonic stem] cells. Within a week, the cells began to form small vesicles and differentiate into two different tissue types: Cells on one side of the vesicles formed the mechanically rigid pigment epithelium, while cells on the other side differentiated into a more flexible tissue that folded inward in the shape of an embryonic optic cup - the retina's precursor.

As you can see, researchers remain a long way away from growing a transplant-ready human retina from cells alone - but this is still an important step forward in the path towards producing such a thing. What is learned here will also inform efforts to build the thousand other tissue types we'd like to be able to produce from scratch.

The Methuselah Foundation invests in a variety of companies, and one of them is Silverstone Solutions. Here the Foundation notes a demonstration of the company's product: "In what is the largest single-hospital kidney swap in the history of California, five patients received five kidneys from healthy donors in a marathon series of operations on Friday, April 1st 2011 ... 'Paired donation' is the procedure that makes it possible, a relatively new phenomenon in transplantation surgery that allows for a live kidney going to someone who has a friend or relative willing to donate an organ not compatible for them but a match for someone else. The donor matches one who needs a kidney and that patient's incompatible donor matches someone else and so on, like a chain. ... Imagine that - multiple lives being extended in one fell swoop! This is one of many reasons why Methuselah Foundation has proudly invested in Silverstone Matchmaker, a break-through computer software that makes the pairings possible. It quickly computes the myriad of possible matches in a pool of prospective donors and recipients, minimizing time and effort that the transplant center needs to reach this goal. ... That is why we proudly extend an angel financing arm, funding the development of the bleeding-edge improvements to the Silverstone technology called MatchGrid. This event is in keeping with Methuselah Foundation's strategy of making investments in life-extending technologies that work RIGHT NOW (dangit!) and that also have long term positive implications for general life extension in the tissue engineering realm. Our long term vision for this technology? We hope that its massive and super performance data management system will eventually play a role in the an envisioned 'Postscript' language that can send printing instructions for creating new tissues and eventually organs to be used by tissue printers such as Organovo's sci-fi worthy 3D tissue printer, another founding angel investment by you, the donors of Methuselah Foundation."

http://blog.methuselahfoundation.org/2011/04/hot_dog_a_record-breaking_5-transplant_kidney_swap.html

The Methuselah Foundation invests in a variety of companies, and one of them is Silverstone Solutions. Here the Foundation notes a demonstration of the company's product: "In what is the largest single-hospital kidney swap in the history of California, five patients received five kidneys from healthy donors in a marathon series of operations on Friday, April 1st 2011 ... 'Paired donation' is the procedure that makes it possible, a relatively new phenomenon in transplantation surgery that allows for a live kidney going to someone who has a friend or relative willing to donate an organ not compatible for them but a match for someone else. The donor matches one who needs a kidney and that patient's incompatible donor matches someone else and so on, like a chain. ... Imagine that - multiple lives being extended in one fell swoop! This is one of many reasons why Methuselah Foundation has proudly invested in Silverstone Matchmaker, a break-through computer software that makes the pairings possible. It quickly computes the myriad of possible matches in a pool of prospective donors and recipients, minimizing time and effort that the transplant center needs to reach this goal. ... That is why we proudly extend an angel financing arm, funding the development of the bleeding-edge improvements to the Silverstone technology called MatchGrid. This event is in keeping with Methuselah Foundation's strategy of making investments in life-extending technologies that work RIGHT NOW (dangit!) and that also have long term positive implications for general life extension in the tissue engineering realm. Our long term vision for this technology? We hope that its massive and super performance data management system will eventually play a role in the an envisioned 'Postscript' language that can send printing instructions for creating new tissues and eventually organs to be used by tissue printers such as Organovo's sci-fi worthy 3D tissue printer, another founding angel investment by you, the donors of Methuselah Foundation."

http://blog.methuselahfoundation.org/2011/04/hot_dog_a_record-breaking_5-transplant_kidney_swap.html

Researchers continue to investigate how to replicate the limb regeneration found in lower animals: "Move over, newts and salamanders. The mouse may join you as the only animal that can re-grow their own severed limbs. Researchers are reporting that a simple chemical cocktail can coax mouse muscle fibers to become the kinds of cells found in the first stages of a regenerating limb. Their study, the first demonstration that mammal muscle can be turned into the biological raw material for a new limb ... their 'relatively simple, gentle, and reversible' methods for creating the early stages of limb regeneration in mouse cells 'have implications for both regenerative medicine and stem cell biology.' In the future, they suggest, the chemicals they use could speed wound healing by providing new cells at the injured site before the wound closes or becomes infected. Their methods might also shed light on new ways to switch adult cells into the all-purpose, so-called 'pluripotent' stem cells with the potential for growing into any type of tissue in the body. The scientists describe the chemical cocktail that they developed and used to turn mouse muscle fibers into muscle cells. [They] then converted the muscle cells turned into fat and bone cells. Those transformations were remarkably similar to the initial processes that occur in the tissue of newts and salamanders that is starting to regrow severed limbs."

Link: http://www.eurekalert.org/pub_releases/2011-04/acs-scc040611.php

You might recall that the Immortality Institute raised funds for a test of laser ablation of lipofuscin, to run on nematode worms using commercially available laser equipment:

The good news for today is that the longevity science grassroots centered at the Immortality Institute have successfully raised $8,000 to fund research into laser ablation of lipofuscin. Those funds will be matched up to $16,000 at the SENS Foundation and put towards work on a method of eliminating one form of damaging metabolic byproducts that build up with age.

Lipofuscin is the name given to a collection of various waste products of metabolism that are hard for the body to break down. They build up inside cells, collecting in the recycling mechanisms of lysosomes and causing cellular housekeeping to progressively fail over time. Ways to safely break down lipofuscin are very much required as a part of the envisaged package of future rejuvenation biotechnology that can prevent and reverse aging.

One proposed methodology for tackling lipofuscin is the use of pulsed laser light targeted at very specific molecules and molecular bonds: in theory, it should be possible to significantly impact lipofuscin levels without harming the cells that contain this gunk. Whether this is the case in practice remains to be seen, but it is an approach well worth testing: after all, lasers are already routinely used in dermatology to achieve conceptually similar goals, and the cost of this test is minimal in the grand scheme of things. Hence the laser ablation project funded by forward-looking donor and organized by the Immortality Institute.

You'll find recent updates on the state of the laser ablation test in the Longecity thread for the project:

Here is the basic agenda for the remainder of the project:

1) Test the effect of 8ns pulses on worm lifespan, at many different intensities. ... The beam coming straight out of the laser has terrific coherence and a nice tophat profile, which although it is 8ns, which is a little harsh, it is wonderfully consistent, great at destroying pigments, and we can rest assured that all worms on the slide are getting the exact same exposure every time.

2) Examine effect on worm activity/livelihood. Since the worms grow distinctively and progressively less active in the 2nd half of their life, this can be used to roughly assess quality of life changes; i.e. if worms are all dying at the same time, but at 75% lifespan, laser-treated groups are still quite active, this could be seen as a definite extension of useful lifespan.

3) Examine changes in pigmentation, if any. I may even be able to rig up a crude blacklight setup and get some fluorescence going. Or we could lop two months of the end of the 8-month project and buy a basic fluorescence scope with the extra $2500

...

4) Assess the effect of laser treatment on a more long-lived strain of worms (such as DAF-16 mutants), as well as the wild-type. This could provide useful clues as to what is going on, whichever way the results go.

...

It's still taking awhile to breed more DA1116 worms. I can see how this is going to go - things are going to stretch out a bit, partly due to my schedule and partly due to using long-lived worms, and the nature of lifespan experiments in general. Therefore I propose using experiments as milestones instead of sticking to a fixed weekly or monthly schedule. Thus the project will span at least 8 complete lifespan experiments, regardless of how long it takes to complete them. The remaining 'monthly' salary and expense checks could be sent at the start of experiments 3, 5 and 7 - which will doubtless end up being more than one month apart. This definitely seems more appropriate to me - that way all of our gracious donors get the same amount of science for their money, regardless of how long it takes.

The fluorescence scope may or may not be purchased for this project, depending on how our financial situation pans out on this end. It may end up being budgeted as part of a future project proposal instead; but we can cross that bridge when we get there.

I'll let everyone know as soon as the worm zapping begins.

One of the Immortality Institute volunteers visited the lab recently, and so you'll find photographs of the equipment, work area, and researcher in the thread to go along with the updates.

By way of a reminder, the Institute continues to raise funding for their next project, an investigation of microglia transplantation as a therapy for age-related neurodegeneration. $5,500 of the needed $8,000 has been raised, and futher donations are very welcome. Every dollar donated will be matched by an additional dollar from the Institute and its sponsors, so that the completed fundraiser will send $16,000 to the laboratory that will carry out the research:

Cognitive functions of the brain decline with age. One of the protective cell types in the brain are called microglia cells. However, these microglia cells also loose function with age. Our aim is to replace non-functional microglia [in mice] with new and young microglia cells derived from adult stem cells.

...

The full PDF format research proposal is available: the work will be carried out by a graduate research assistant and will cost $16,000. This is the essence of our present era of biotechnology: a task that would have occupied a whole laboratory and its equipment in the 1980s, and cost a great deal of money if it was even possible at all, is now something that a skilled graduate-level life scientist can organize and run himself within an established lab.

You might recall that the Immortality Institute raised funds for a test of laser ablation of lipofuscin, to run on nematode worms using commercially available laser equipment:

The good news for today is that the longevity science grassroots centered at the Immortality Institute have successfully raised $8,000 to fund research into laser ablation of lipofuscin. Those funds will be matched up to $16,000 at the SENS Foundation and put towards work on a method of eliminating one form of damaging metabolic byproducts that build up with age.

Lipofuscin is the name given to a collection of various waste products of metabolism that are hard for the body to break down. They build up inside cells, collecting in the recycling mechanisms of lysosomes and causing cellular housekeeping to progressively fail over time. Ways to safely break down lipofuscin are very much required as a part of the envisaged package of future rejuvenation biotechnology that can prevent and reverse aging.

One proposed methodology for tackling lipofuscin is the use of pulsed laser light targeted at very specific molecules and molecular bonds: in theory, it should be possible to significantly impact lipofuscin levels without harming the cells that contain this gunk. Whether this is the case in practice remains to be seen, but it is an approach well worth testing: after all, lasers are already routinely used in dermatology to achieve conceptually similar goals, and the cost of this test is minimal in the grand scheme of things. Hence the laser ablation project funded by forward-looking donor and organized by the Immortality Institute.

You'll find recent updates on the state of the laser ablation test in the Longecity thread for the project:

Here is the basic agenda for the remainder of the project:

1) Test the effect of 8ns pulses on worm lifespan, at many different intensities. ... The beam coming straight out of the laser has terrific coherence and a nice tophat profile, which although it is 8ns, which is a little harsh, it is wonderfully consistent, great at destroying pigments, and we can rest assured that all worms on the slide are getting the exact same exposure every time.

2) Examine effect on worm activity/livelihood. Since the worms grow distinctively and progressively less active in the 2nd half of their life, this can be used to roughly assess quality of life changes; i.e. if worms are all dying at the same time, but at 75% lifespan, laser-treated groups are still quite active, this could be seen as a definite extension of useful lifespan.

3) Examine changes in pigmentation, if any. I may even be able to rig up a crude blacklight setup and get some fluorescence going. Or we could lop two months of the end of the 8-month project and buy a basic fluorescence scope with the extra $2500

...

4) Assess the effect of laser treatment on a more long-lived strain of worms (such as DAF-16 mutants), as well as the wild-type. This could provide useful clues as to what is going on, whichever way the results go.

...

It's still taking awhile to breed more DA1116 worms. I can see how this is going to go - things are going to stretch out a bit, partly due to my schedule and partly due to using long-lived worms, and the nature of lifespan experiments in general. Therefore I propose using experiments as milestones instead of sticking to a fixed weekly or monthly schedule. Thus the project will span at least 8 complete lifespan experiments, regardless of how long it takes to complete them. The remaining 'monthly' salary and expense checks could be sent at the start of experiments 3, 5 and 7 - which will doubtless end up being more than one month apart. This definitely seems more appropriate to me - that way all of our gracious donors get the same amount of science for their money, regardless of how long it takes.

The fluorescence scope may or may not be purchased for this project, depending on how our financial situation pans out on this end. It may end up being budgeted as part of a future project proposal instead; but we can cross that bridge when we get there.

I'll let everyone know as soon as the worm zapping begins.

One of the Immortality Institute volunteers visited the lab recently, and so you'll find photographs of the equipment, work area, and researcher in the thread to go along with the updates.

By way of a reminder, the Institute continues to raise funding for their next project, an investigation of microglia transplantation as a therapy for age-related neurodegeneration. $5,500 of the needed $8,000 has been raised, and futher donations are very welcome. Every dollar donated will be matched by an additional dollar from the Institute and its sponsors, so that the completed fundraiser will send $16,000 to the laboratory that will carry out the research:

Cognitive functions of the brain decline with age. One of the protective cell types in the brain are called microglia cells. However, these microglia cells also loose function with age. Our aim is to replace non-functional microglia [in mice] with new and young microglia cells derived from adult stem cells.

...

The full PDF format research proposal is available: the work will be carried out by a graduate research assistant and will cost $16,000. This is the essence of our present era of biotechnology: a task that would have occupied a whole laboratory and its equipment in the 1980s, and cost a great deal of money if it was even possible at all, is now something that a skilled graduate-level life scientist can organize and run himself within an established lab.

Researchers have demonstrated that "damaged muscle tissues treated with satellite cells in a special degradable hydrogel showed satisfactory regeneration and muscle activity. Muscle activity in repaired muscle in a mouse model was comparable with untreated muscles. ... Satellite cells (SCs), freshly isolated or transplanted within their niche, are presently considered the best source for muscle regeneration. They are located around existing muscles. Hence, a patient's own cells can be used, from a muscle biopsy. ... A key issue for regeneration is how cells grow as a structure, as they usually require some form of framework. A hard framework would impede muscle growth and muscle cell penetration. The hydrogel, by contrast, provides a supportive structural skeleton but degrades quickly as muscle tissue returns and the support becomes unnecessary. The gel is initially liquid, hardens in place under UV light, and is easily penetrated by muscle cells. ... This is using the patient's own cells, without any lengthy culturing process, which means we could take a biopsy, produce the cells in a couple of hours, and implant them where needed - it can be done in theatre as one process. Using the patient's own cells eliminates any tissue rejection. ... The focus for initial clinical research in humans will be relatively small muscles at first, like deformities in the face and palate, or in the hand. It will be technically more demanding to grow larger muscles with more structure, which would require their own nerves and blood supply."

Link: http://www.ucl.ac.uk/news/news-articles/1103/31031101

The Methuselah Generation is a documentary film in progress, far enough along that the filmmaker is putting out early versions: "Is aging a disease that can be cured? Is it possible to live forever? Even if we could, should we? The Methuselah Generation (working title) is a 3D verite documentary about the science and philosophy of Life Extension - the scientific hypothesis that individuals may be capable of extending human life beyond anything humans have yet imagined. The story will follow a select few individuals at the forefront of this movement as well as those skeptical and antagonistic toward the goals of life extension. The film will follow five protagonists as they progress with their movement to change humanity. Through intimate interviews, observational shooting and provocative imagery, this character-based 3D documentary will explore the big philosophical ideas of Life Extension, while also examining the scientific feasibility - the film will explore the what, how and (most significantly) the WHY of long-lived humans."

Link: http://davidalvarado.info/le.html

The evolutionary view of cancer and aging is that these end points stand in opposition: complex organisms such as mammals evolve to some point of balance between risk of cancer and certainty of accelerated aging. This happens because the mechanisms that suppress cancer also inhibit the necessary regenerative capacity to maintain tissue function: it's largely a matter of how free cells are to divide and multiply, taking into account the increasing levels of damage and mutation with age - which increase the chance of a cancer developing.

In research focused on this balance between aging and cancer, two genes - and the proteins they produce - are especially important: p53 and p16. Both can suppress cancer, but at the cost of accelerated aging:

• On p53 and Aging
• Understanding a Tumor Suppression Gene

p16 has been particularly interesting of late because it appears to be a plausible candidate for the cancer immunity observed in naked mole rats:

the mole rat's cells express a gene called p16 that makes the cells 'claustrophobic,' stopping the cells' proliferation when too many of them crowd together, cutting off runaway growth before it can start. The effect of p16 is so pronounced that when researchers mutated the cells to induce a tumor, the cells' growth barely changed

Unfortunately, as recent research illustrates, making use of this knowledge isn't as easy as just ramping up p16 gene expression in other mammal species:

"I didn't anticipate that increased production of the p16 tumor suppressor protein would so readily promote aging," says Enders, who led the study. "The p16 protein has been previously associated with aging, and we know its expression increases during late stages of aging. But the idea that its expression would be sufficient to generate features of aging was surprising."

Although scientists know that loss of p16 is associated with numerous human tumors, they know much less about the function of p16 in normal cells and tissues. To explore this, Enders' team engineered a strain of mice that enables them to control p16 expression in various tissues and at various times in an animal's lifespan. They quickly found that turning on p16 blocked cell proliferation in normal tissues.

The implications of blocked cell proliferation emerged when they expressed p16 in animals that were not yet fully mature. "They developed features of premature aging," Enders says. "To my knowledge, this is the first model that induces striking characteristics of premature aging where there is no macromolecular damage. The premature aging appears to be the result of blocking cell proliferation."

In this respect, p16 is very similar in behavior to p53. But that in fact means that there is great promise inherent in p16 research: a few years ago, Spanish researchers engineered their way around the aging-cancer balance in mice for p53, producing mice that suffered less cancer and lived 50% longer than normal. Trying a similar approach with p16 sounds very plausible. It is also possible that their work is analogous to the biology of naked mole-rats, animals that manage to live vastly longer than the members of other similarly sized rodent species, and this despite their evolved usage of p16 and apparently complete immunity to cancer. Equally, mole-rats might exhibit yet another completely different configuration of mammalian biology - one that it may soon be possible to reverse engineer and test in mice.

Answers to this sort of speculation still lie in the near future, but research into the biochemistry of p16 and p53 is worth keeping an eye on. Few other methodologies can claim to have extended healthy life in mice by as much as that mentioned above, and, furthermore, somewhere in the biology of these species lies a way to simply turn off cancer.