A thought for the day: nobody out there is seriously arguing for the impossibility of radical life extension, and I don't think anyone has been for quite some time. It is a given in the present diffuse discussion on the future of medicine and human longevity that at some point advances in biotechnology and nanotechnology will lead to greatly extended lives: centuries and longer lived in good health and vigor. Aging will be brought under control by medicine, like any number of other once intractable medical conditions.

It wasn't always this way. People in past centuries might have hoped for the plausibility of radical life extension, but couldn't have said in certainty that it was possible. We, on the other hand, know far more about physics, chemistry, and biology: we know that there is no wall created by the way the universe works standing in our way. The only reason we presently age and suffer is because we haven't yet advanced far enough down the path of biotechnology that is clearly visible and well understood. Aging is, at root, a matter of atoms and molecules in the wrong place and the wrong configuration. Moving atoms and molecules around to order, en masse, and with precision, is a task that we know is possible. We do it all the time, and are learning ever greater finesse with each passing decade.

Yesterday the tools were found molecules that happened to do something useful with other molecules. Today we make use of designed molecules for particular operations, knowing much more about the molecular machinery of our cells. Tomorrow the biotechnologists will build and repair complex molecular machinery that performs far more effectively than our evolved biology.

Thus discussions on the engineering of human longevity focus on how, when, and (sadly) whether it should be done at all. I see great strategic importance in the right groups gaining ground in the "how" discussion - we're all going to age to death just like our ancestors if the scientific community remains focused on metabolic manipulation to slow damage accumulation rather than the repair of damage exemplified by SENS, for example. Similarly if there are not good inroads made in growing the community of researchers interested in SENS and related lines of research.

Discussions on "when" can probably be skipped as lacking rigor: no-one knows. All the meaningful timelines depend greatly on seeds sown now that will only bear fruit in the 2030s - the course of twenty years remains a matter of long term planning and great uncertainty in specific outcomes while we're stuck living lives that top out at a century (and that with great luck). The beginnings of a larger research community, the outcome of the debate over strategy in longevity research, and so forth. It is interesting to ponder and plot the windings of future events, but that time is probably better spent on influencing the "how" discussion or materially contributing to progress.

As to the discussion on whether engineering longevity is desirable, or should be blocked by people in power - I think it never hurts to take a little time to oppose such lines of thought. Unthought opposition to extending human life or even simply intervening in the disease of aging is widespread, and success in building the research communities and funding institutions of the next few decades depends on a certain degree of broad public support.

But all that said, no-one out there is seriously arguing that radical life extension is impossible.

Damage to mitochondrial membranes is an important feature of the complex process by which mitochondrial DNA damage contributes to aging. It is known that differences in membrane composition may be an important factor in species of unusual longevity, such as naked mole rats. Here is another open access study on this topic: "The cellular energy produced by mitochondria is a fundamental currency of life. However, the extent to which mitochondrial (mt) performance (power and endurance) is adapted to habitats and life-strategies of vertebrates is not well-understood. A global analysis of mt genomes revealed that hydrophobicity (HYD) of mt membrane proteins (MMPs) is much lower in terrestrial vertebrates than in fishes and shows a strong negative correlation with serine/threonine composition (STC). Here, we present evidence that this systematic feature of MMPs was crucial for the evolution of large terrestrial vertebrates with high aerobic capacity. An Arrhenius-type equation gave positive correlations between STC and maximum lifespan (MLS) in terrestrial vertebrates ... In particular, marked STC-increases in primates (especially hominoids) among placentals were associated with very high MLS-values. We connected these STC-increases in MMPs with greater stability of respiratory complexes." This sort of study should be viewed as supporting evidence for the importance of work on repairing mitochondrial damage - confirmation of the importance of mitochondria to aging and longevity.

Link: http://gbe.oxfordjournals.org/content/early/2011/08/10/gbe.evr079.abstract

Uncoupling proteins are involved in the processes by which metabolism determines natural longevity through their effects on mitochondrial activity, and are of interest to calorie restriction researchers: "The brown fat specific UnCoupling Protein 1 (UCP1) is involved in thermogenesis, a process by which energy is dissipated as heat in response to cold stress and excess of caloric intake. Thermogenesis has potential implications for body mass control and cellular fat metabolism. In fact, in humans, the variability of the UCP1 gene is associated with obesity, fat gain and metabolism. Since regulation of metabolism is one of the key-pathways in lifespan extension, we tested the possible effects of UCP1 variability on survival. Two polymorphisms (A-3826G and C-3740A), falling in the upstream promoter region of UCP1, were analyzed in a sample of 910 subjects from southern Italy (475 women and 435 men; age range 40-109). By analyzing haplotype specific survival functions we found that the A-C haplotype favors survival in the elderly. Consistently, transfection experiments showed that the luciferase activity of the construct containing the A-C haplotype was significantly higher than that containing the G-A haplotype. Interestingly, the different UCP1 haplotypes responded differently to hormonal stimuli. The results we present suggest a correlation between the activity of UCP1 and human survival, indicating once again the intricacy of mechanisms involved in energy production, storage and consumption as the key to understanding human aging and longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21827845

Wealth, in the most general sense, is a blade of many edges. Let us consider food, for example, which has moved over the centuries of growing wealth from being expensive and unreliably supplied to its present state of being cheap and exceedingly reliable in supply in all the stable regions of the world. That has been a passage of stages: from the bootstrapping of early longevity gains and better land use in the 1700s, all the way through to the stunning advances in productivity that resulted from applications of the first wave of modern biotechnology in the 60s and 70s. Unfortunately we humans are not well adapted for an environment of abundant and cheap food: by following our instincts and ingrained preferences we wind up fat and sedentary, a state that causes significant harm to health and longevity.

This is one of those temporary issues, a matter of a handful of decades. Medical biotechnology will catch up to the new demands of the population, and at some point humans will learn to alter themselves such that there are no longer any detrimental consequences to overeating, or being fat, or being sedentary. That isn't so far away: perhaps fifty years at the outside. In the meanwhile there is willpower or there is a shorter, less healthy life. Your choice.

The data on what exactly excess body fat will do to you - on average, statistically speaking - has been growing over the past years. Fat is metabolically active, an eager and pushy partner in the feedback loops and controlling systems of your metabolism. A lot of what it does is bad in the long term: spurring chronic inflammation, for example. Even comparatively early in life, putting on the pounds and keeping them on for years at a time has a sizable impact on your risk of later suffering all of the most common age-related conditions. Failing to exercise appears to be just as bad in a whole different set of ways.

In any case, here is recently published research from a long-term study that adds yet more data on the costs of fat tissue - and thus the costs of the lifestyle choices needed to gain and maintain that fat tissue:

While some past studies have shown that persons carrying a few extra pounds in their 70s live longer than their thinner counterparts, a new study that measured subjects' weight at multiple points over a longer period of time reveals the opposite. Research from Adventist Health Studies recently published in the Journal of the American Geriatrics Society showed that men over 75 with a body mass index (BMI) greater than 22.3 had a 3.7-year shorter life expectancy, and women over 75 with a BMI greater than 27.4 had a 2.1-year shorter life expectancy. Generally, a BMI between 18.5 and 24.9 is considered normal weight, and a BMI of 25 to 29.9 is considered overweight. A BMI of 30 or more is considered obese.

Previous work in this area by others found a protective association for a high body weight among the elderly. Pramil N. Singh, DrPH, lead author of the paper and an associate professor in the School of Public Health at Loma Linda University, says the data from many past studies is problematic because only a single baseline measure of weight was taken, which does not account for weight changes or how weight changes affect life expectancy. Additionally, most past studies had mortality surveillance of fewer than 19 years, which analyses have shown to be an inadequate amount of time to study risks associated with weight.

"We had a unique opportunity to do 29 years of follow-up with a cohort that was also followed for mortality outcomes," Dr. Singh said. "Across this long period of time, we had multiple measures of body weight, which provided a more accurate assessment."

A novel way to manipulate stem cells: "Though the heart is known to contain some stem cells, they have a very limited ability to repair damage caused by a heart attack [and] researchers have had to look elsewhere. One of the first efforts to use stem cells to reduce heart scarring involved harvesting them from the bone marrow and inserting them back into the heart muscle, close to the heart's blood supply, but this had limited success. Prof. Oron, who has long used low level lasers to stimulate stem cells to encourage cell survival and the formation of blood vessels after a heart attack, was inspired to test how laser treatments could also work to heal the heart. He and his fellow researchers tried different methods, including treating the heart directly with low level lasers during surgery, and 'shining' harvested stem cells before injecting them back into the body. But he was determined to find a simpler method. After a low-level laser was 'shined' into a person's bone marrow - an area rich in stem cells - the stem cells took to the blood stream, moving through the body and responding to the heart's signals of distress and harm ... Once in the heart, the stem cells used their healing qualities to reduce scarring and stimulate the growth of new arteries, leading to a healthier blood flow. To determine the success of this method, Prof. Oron performed the therapy on an animal model. Following the flow of bone marrow stem cells through the use of a fluorescent marker, the researchers saw an increase in stem cell population within the heart, specifically in the injured regions of the heart. The test group that received the shining treatment showed a vastly higher concentration of cells in the injured organ than those who had not been treated with the lasers."

Link: http://www.eurekalert.org/pub_releases/2011-08/afot-ta081011.php

The I'm Not Dead Yet (INDY) gene is one of the earlier longevity genes discovered by researchers in course of investigating the effects of calorie restriction. Here is a recent update: "It is known that excess calorie consumption leads to obesity, insulin resistance and increased mortality, whereas calorie restriction reduces accumulation of body fat and improves cellular energy balance and insulin action - reversing obesity and type 2 diabetes, delaying the aging process, and prolonging life in primates and many other species. It has also been shown in the past that reduced expression of the so-called 'INDY' gene in D. Melanogaster flies and C. elegans worms promotes longevity in a manner similar to calorie restriction. But until now, the cellular mechanism by which this happens was unknown. [Researchers] generated a mouse with the so-called 'INDY' gene deleted. Loss of the gene altered chemical levels in the cellular signaling network in a way that improved mitochondrial action in the liver, metabolism of fatty acids, and cellular energy transport. Overall, these traits protected the mice from diet-related accumulation of body fat and insulin resistance that evolve, as we age, into type 2 diabetes. Discovering how deletion of the INDY gene would impact mitochondrial metabolism in the liver was key, because that is the main organ where the INDY gene does its work."

Link: http://opac.yale.edu/news/article.aspx?id=8772

The immune system is a powerful tool for the selective destruction of unwanted cells, and researchers are a fair way down the road of engineering the activity of the immune system to form therapies. You might look at granulocyte transplant therapy as an example of the sort of tools that are under development. Here is an article on another line of research that has just reached the stage of early tests in humans:

In the research published Wednesday, doctors at the University of Pennsylvania say the treatment made the most common type of leukemia completely disappear in two of the patients and reduced it by 70 percent in the third. In each of the patients as much as five pounds of cancerous tissue completely melted away in a few weeks, and a year later it is still gone.

...

the researchers removed certain types of white blood cells that the body uses to fight disease from the patients. Using a modified, harmless version of HIV, the virus that causes AIDS, they inserted a series of genes into the white blood cells. These were designed to make to cells target and kill the cancer cells. After growing a large batch of the genetically engineered white blood cells, the doctors injected them back into the patients. In similar past experimental treatments for several types of cancer the re-injected white cells killed a few cancer cells and then died out. But the Penn researchers inserted a gene that made the white blood cells multiply by a thousand fold inside the body. The result, as researcher June put it, is that the white blood cells became "serial killers" relentlessly tracking down and killing the cancer cells in the blood, bone marrow and lymph tissue.

An editorial and research paper are available if you are interested in delving further into the details. Unfortunately this work suffers from much the same problem as efforts to develop granulocyte transplant therapies, which is that there are next to no sources of funding for research groups at the cutting edge of immunotherapy. The article relates what is a sadly common story in this part of the scientific community:

So why has this remarkable treatment been tried so far on only three patients? Both the National Cancer Institute and several pharmaceutical companies declined to pay for the research. Neither applicants nor funders discuss the reasons an application is turned down. But good guesses are the general shortage of funds and the concept tried in this experiment was too novel and, thus, too risky for consideration. The researchers did manage to get a grant from the Alliance for Cancer Gene Therapy, a charity founded by Barbara and Edward Netter after their daughter-in-law died of cancer. The money was enough to finance the trials on the first three patients.

This is a good example of how philanthropy modeled on venture investment - backing a range of early stage, high risk, high reward projects - can help break up the log-jams that result from institutional reluctance to fund the cutting edge in any field. The larger an institution, the more they will tend towards only backing the safe choices, but by doing that they ensure that the backing of their resources has little chance of producing radical change. Hopefully other projects, such as work on granulocyte based therapies, can find the connections needed to benefit from similar sources of funding and vision.

Why are hearts in humans and other higher animals not able to regenerate like salamander hearts? Answering that question would be a step on the road to recreating that ability when needed: "A new study has shed light on why adult human cardiac cells lose their ability to proliferate, perhaps explaining why our heart have little regenerative capacity. The study, done in cell lines and mice, may lead to methods of reprogramming a patient's own cardiac myocytes, or muscle cells, within the heart itself to create new muscle to repair damage ... Recent research suggests that mammals do have the ability to regenerate the heart for a very brief period, about the first week of life. ... During human development, cardiac myocytes are made by progenitor stem cells and proliferate to form the heart. Once the heart is formed, the myocytes transform from immature cells into mature cells that cannot proliferate. That's not so for newts and salamanders, whose cardiac myocytes can go back and forth between immature, or primitive, states to proliferate and repair damage and then revert back into mature cells once the damage is repaired. [Researchers believe] the reason adult human cardiac myocytes can't do this is quite simple - when the myocytes are in a more primitive state, they are not as good at contracting, which is vital for proper heart function. Because humans are much larger than newts and salamanders, we needed more heart contraction to maintain optimum blood pressure and circulation."

Link: http://timesofindia.indiatimes.com/life-style/health-fitness/health/articleshow/9553629.cms

Another of the many benefits of exercise: a study "shows that a small amount of physical exercise could profoundly protect the elderly from long-term memory loss that can happen suddenly following infection, illnesses or injury in old age. ... aging rats that ran just over half a kilometer each week were protected against infection-induced memory loss. ... Our research shows that a small amount of physical exercise by late middle-aged rats profoundly protects against exaggerated inflammation in the brain and long-lasting memory impairments that follow a serious bacterial infection. Strikingly, this small amount of running was sufficient to confer robust benefits for those that ran over those that did not run. This is an important finding because those of advanced age are more vulnerable to memory impairments following immune challenges such as bacterial infections or surgery. With baby boomers currently at retirement age, the risk of diminished memory function in this population is of great concern. Thus, effective noninvasive therapies are of substantial clinical value. ... Past research has shown that exercise in humans protects against declines in cognitive function associated with aging and protects against dementia. Researchers also have shown that dementia is often preceded by bacterial infections, such as pneumonia, or other immune challenges. ... Previous research has shown that immune cells of the brain, called microglia, become more reactive with age. When the older rats in the study encountered a bacterial infection, these immune cells released inflammatory molecules called cytokines in an exaggerated and prolonged manner. ... In the current study we found that small amounts of voluntary exercise prevented the priming of microglia, the exaggerated inflammation in the brain, and the decrease of growth factors."

Link: http://www.eurekalert.org/pub_releases/2011-08/uoca-sao080911.php

Good news is now arriving frequently from the tissue engineering community, who really seem to be hitting their stride of late, especially when it comes to muscle. Recreating structured muscle is the simple stuff on a relative scale of difficulty - at least in comparison to lungs and other intricate organs - but this is still a very challenging task. Dumb muscle isn't just dumb muscle: it has to be the right shape, have the right nerve structures, the right distribution of tiny blood vessels, the right layering and fiber types, and so forth. Don't underestimate just how much work was involved in coming to the point at which researchers can announce this latest advance:

Researchers have built the first functional anal sphincters in the laboratory, suggesting a potential future treatment for both fecal and urinary incontinence. Made from muscle and nerve cells, the sphincters developed a blood supply and maintained function when implanted in mice.

...

Current options for repair of the internal anal sphincter include grafts of skeletal muscle, injectable silicone material or implantation of mechanical devices, all of which have high complication rates and limited success. To engineer an internal anal sphincter in the laboratory, the researchers used a small biopsy from a human sphincter and isolated smooth muscle cells that were then multiplied in the lab. In a ring-shaped mold, these cells were layered with nerve cells isolated from mice to build the sphincter. The mold was placed in an incubator for nine days, allowing for tissue formation. The entire process took about six weeks.

Numerous laboratory tests of the engineered sphincters, including stimulating the nerve cells, showed normal tissue function, such as the ability to relax and contract. The sphincters were then implanted just under the skin of mice to determine how they would respond in the body. Mice with suppressed immune systems were selected so that there would be no issues with rejection. ... After 25 days of implantation, each sphincter was re-tested and also compared with the animals' native sphincters. The engineered sphincters had developed a blood vessel supply and continued to function like native tissue.

As the news release points out, this is one of the areas where the available prosthetic alternatives are just not that great; engineering a replacement sphincter in machinery is a hard challenge at our present level of technological prowess. So that a research team has constructed a functional biological sphincter is very promising - and this is especially true given that there are dozens of sphincters scattered throughout the body. It is an oft-reused structure, and being able to build any one type of sphincter from a patient's own cells implies that building the others is also a very realistic goal. So all in all, this is an encouraging example of progress in the field.