Around these parts Aubrey de Grey and the SENS Foundation should require no introduction. His advocacy and the Foundation's work on the science of repairing aging is well known, and has been mentioned here at Fight Aging! too many times to count. In my eyes, the Strategies for Engineered Negligible Senescence (SENS) continue to be the best extant plan for extending human life span as rapidly as possible - and within our lifetimes. The more funding that is devoted to realizing that plan, the better all of our futures will be.

I noticed that a podcast interview with de Grey is up at the Singularity Weblog:

Last time I had Dr. Aubrey de Grey on Singularity 1 on 1 the interview turned out to be a hit. In fact it is still by far the most popular podcast that I have done and the audio file has been listened to or downloaded over 30,000 times. Given Aubrey's popular appeal and the importance of his work, it is no surprise that I am very happy to have him back for a second interview. ... During this conversation I ask Dr. de Grey to discuss issues such as: the term natural death and its impact; the publicity and importance of two long-awaited documentaries about Ray Kurzweil - Transcendent Man and The Singularity is Near; traditional metabolic and more recent DNA tests such as the ones done by 23andMe and others; the slow developmental process of new drugs and therapies, and the problems of taking them from testing in lab rats to humans; the Thomas Malthus argument of overpopulation and Aubrey's reply to it.

Head on over there to watch or listen.

The investigation of the mechanisms of calorie restriction continues apace. Here, researchers "report for the first time that deactivation of a protein called CRTC1 in roundworms increases their lifespan, most likely mediating the effects of calorie restriction. Previously, researchers knew hunger promoted longevity by activating an enzyme called AMPK, which senses that food is scarce and pushes cells into a low energy state. ... We knew AMPK was a major energy sensor but didn't know what it was talking to. Our goal was to understand the genetic circuitry that registered that response. ... It was clear that one pathway that coordinated metabolism with growth in response to nutrients was AMPK signaling. Studies had also suggested that AMPK might regulate lifespan in worms. What was not known was what factors downstream of AMPK mediated those effects. ... they searched the genome of Caenorhabditis elegans for likely AMPK targets, and identified one suspect encoding a protein called CRTC1, which was expressed at the same time and place as AMPK. To determine if CRTC1 played any role in lifespan, the team fed worms an inhibitory RNA engineered to deplete them of CRTC1 protein. When they measured the worms' lifespan-normally about 3 weeks-they found that worms fed the anti-CRTC1 RNA lived a whopping 40% longer, suggesting that AMPK retards aging by antagonizing CRTC1 activity. ... AMPK deactivated CRTC1 by adding phosphates to a specific region of the CRTC1 protein, an effect equivalent to eliminating CRTC1 altogether. Likewise, when the worms were fed an inhibitory RNA depleting them of an enzyme that lops off the CRTC1 phosphates, they lived longer, showing that AMPK and the lopper - known to scientists as calcineurin - determine lifespan by controlling the extent to which CRTC1 is phosphorylated."

Link: http://www.newswise.com/articles/hungering-for-longevity-salk-scientists-identify-the-confluence-of-aging-signals

From ScienceDaily: "It has been long known that stress plays a part not just in the graying of hair but in hair loss as well. ... Now, a team [that] was investigating how stress affects gastrointestinal function may have found a chemical compound that induces hair growth by blocking a stress-related hormone associated with hair loss - entirely by accident. ... Our findings show that a short-duration treatment with this compound causes an astounding long-term hair regrowth in chronically stressed mutant mice. This could open new venues to treat hair loss in humans through the modulation of the stress hormone receptors, particularly hair loss related to chronic stress and aging. ... the researchers had been using mice that were genetically altered to overproduce a stress hormone called corticotrophin-releasing factor, or CRF. As these mice age, they lose hair and eventually become bald on their backs, making them visually distinct from their unaltered counterparts. The [researchers] had developed the chemical compound, a peptide called astressin-B, and described its ability to block the action of CRF. ... researchers injected the astressin-B into the bald mice to observe how its CRF-blocking ability affected gastrointestinal tract function. .... About three months later, the investigators returned to these mice to conduct further gastrointestinal studies and found they couldn't distinguish them from their unaltered brethren. They had regrown hair on their previously bald backs."

Link: http://www.sciencedaily.com/releases/2011/02/110216185406.htm

The latest issue of Rejuvenation Research is available online, and it opens with what is perhaps one of the best of points to make in a world in which people are dying all around us:

I welcome Dr. Paula Moreira as a new member of our editorial board, but for the worst possible reason. Moreira has been appointed as a replacement for Mark Smith, a fellow professor at Case Western Reserve University, who tragically died in a car accident late last year. What is even worse is that Smith is not the only loss that the field of biogerontology has suffered in 2010. In fact, I am aware of fully five other researchers who died during 2010. Amir Abramovich (whose Ph.D. advisor has penned a brief obituary that appears later in this issue) and Estela Medrano also succumbed to road accidents. James Joseph died from complications following heart surgery. Chris Heward was the victim of a particularly aggressive esophageal cancer. And Bob Butler died very suddenly of leukemia.

...

I have chosen to highlight these sombre events in this space not only to commemorate lost friends and colleagues. My main reason for doing so is to draw attention to the questionable validity of our tendency to grieve especially intensely for those who die when still highly active. Though I share this tendency, I think it deserves scrutiny, because it is founded on an assumption that profoundly contradicts the motivation for the work to which we, as did the colleagues I have just listed, dedicate our lives.

Aging kills people, just as cars do. There are only two things that distinguish aging from other killers: it kills people very slowly, only after gradually and progressively debilitating them over many years, and it only kills people who were born quite a long time ago. The combination of these features seems to be the only available explanation for why we so meekly and calmly accept the deaths of so vast a number of people from aging, while feeling much more intense anger and despair at the comparatively rare deaths that occur in the industrialized world at younger ages.

...

Is it somehow OK, or at least only a little bit sad, when someone dies of "natural causes" after "a good innings"? I would suggest that it is not OK.

Ageism permeates our societies, and our descendants will look back in disgust and horror at the way in which we allowed our historical legacy of prejudice to suppress and slow down progress towards the biotechnologies of rejuvenation. We younger folk write off the old in so many ways, and in doing so each of us is only sticking the knife into the person we'll be a few decades down the line - and teaching our children to do exactly the same. Every death is a tragedy, but so many people work so hard to pretend otherwise.

Old people suffer from a terrible debilitating medical condition: aging. Why view them any differently than the victims of any other deadly disease? If not weighed down by the degenerations of aging and the knowledge of suffering a certainly terminal condition, elderly folk could contribute greatly to all fields of human endeavor, applying the experience and knowledge of a lifetime - or adeptly applying the savings of a lifetime to fund the work of others. We would all be far wealthier if the ongoing ability to create value offered by human beings was not destroyed after a bare few decades of productivity.

Even if it wasn't the case that it is in our immediate economic self-interest to build rejuvenation biotechnologies, working to cure aging would still be the greatest of charitable causes. No other aspect of human biology or the human condition causes as much pain and death.

Aging is a horror, and it twists our society into further horrors - such as the often shameful ways in which the young treat the old. The sooner that aging can be repaired and removed as a threat to human existence, the better the human condition will become.

From the Monterey Herald: " Within a Northeast Ohio lab, a hairless mouse is growing an ear from the cells of a Wadsworth, Ohio, preschooler. Dr. William Landis, the G. Stafford Whitby Chair of Polymer Science at the University of Akron, is leading groundbreaking, tissue-engineering research to grow human cartilage - first in the lab, now in animals and, eventually, in patients. His work is part of a fast-developing field that could help millions of patients repair injuries, replace worn body parts or fix birth defects with tissue grown from their own cells in the not-so-distant future. ... Kyle Figuray's parents agreed to be the first area participants and donors of his otherwise useless cartilage. The healthy, friendly 5-year-old was born with a congenital defect that caused the exterior ear and ear canal on his right side to develop improperly. Typically, the malformed ear cartilage is discarded as medical waste after it's removed during the first of three procedures to craft a new ear out of rib. Instead, the tissue removed [was] placed inside a vial and shared with Landis' research team, who carefully cleansed the cells and fed them special nutrients to coax them to proliferate in the lab. A few weeks later, enough cells were available for researchers to 'seed' them onto a biodegradable, biocompatible polymer scaffold. A few days later, the seeded ear scaffold was implanted under the skin of a hairless mouse ... The mouse will be studied over the next year to determine how the cells are behaving and progressing toward normal cartilage. If all goes well, the biodegradable polymer scaffold should disappear, leaving behind only Kyle's cartilage cells in the shape of an ear. The hope is that an affected person's cells someday can be harvested, seeded onto similar polymer scaffolds and implanted under the patient's own skin in the abdomen or back until they grow into replacement tissue. At that point, the new tissue could be removed and used to replace the patient's injured or defective tissue."

Link: http://www.montereyherald.com/science/ci_17411698

Research into Laron dwarfism in a population in Ecuador has been taking place for a few years now: "People living in remote villages in Ecuador have a mutation that some biologists say may throw light on human longevity and ways to increase it. The villagers are very small, generally less than three and a half feet tall, and have a rare condition known as Laron syndrome or Laron-type dwarfism. ... though cancer was frequent among people who did not have the Laron mutation, those who did have it almost never got cancer. And they never developed diabetes, even though many were obese, which often brings on the condition. ... [this is] an opportunity to explore in people the genetic mutations that researchers [found] could make laboratory animals live much longer than usual. ... The Laron patients' mutation means that their growth hormone receptor lacks the last eight units of its exterior region, so it cannot react to growth hormone. In normal children, growth hormone makes the cells of the liver churn out another hormone, called insulinlike growth factor, or IGF-1, and this hormone makes the children grow. If the Laron patients are given doses of IGF-1 before puberty, they can grow to fairly normal height. This is where the physiology of the Laron patients links up with the longevity studies that researchers have been pursuing with laboratory animals. IGF-1 is part of an ancient signaling pathway that exists in the laboratory roundworm as well as in people. The gene that makes the receptor for IGF-1 in the roundworm is called DAF-2. And worms in which this gene is knocked out live twice as long as normal."

Link: http://www.nytimes.com/2011/02/17/science/17longevity.html

There is clearly a point in Alzheimer's, and other neurodegenerative diseases, beyond which the damage caused by the condition is irreversible. Neurons die, and in large enough numbers to destroy vast swathes of information held in the brain - the very foundation of who you are, and the vital components of systems needed to live a normal life. All is not gloom, however. Studies in past years have suggested that up to that point, much of the loss of function that accompanies Alzheimers is in principle reversible:

Some evidence suggests that the worst effects of Alzheimer's disease can be repaired - that memories are not destroyed, but rather become inaccessible.

Another recent study adds to this picture:

Amyloid-beta and tau protein deposits in the brain are characteristic features of Alzheimer disease. The effect on the hippocampus, the area of the brain that plays a central role in learning and memory, is particularly severe. However, it appears that the toxic effect of tau protein is largely eliminated when the corresponding tau gene is switched off.

Researchers from the Max Planck Research Unit for Structural Molecular Biology at DESY in Hamburg have succeeded in demonstrating that once the gene is deactivated, mice with a human tau gene, which previously presented symptoms of dementia, regain their ability to learn and remember, and that the synapses of the mice also reappear in part. The scientists are now testing active substances to prevent the formation of tau deposits in mice. This may help to reverse memory loss in the early stages of Alzheimer disease - in part, at least.

For yet another consideration of early to mid-stage Alzheimer's as a form of dynamic blockage of memory access, you might also look at the effects of some newer anti-inflammatory treatments:

The [study from 2008] documents a dramatic and unprecedented therapeutic effect in an Alzheimer's patient: improvement within minutes following delivery of perispinal etanercept, which is etanercept given by injection in the spine.

Putting aside a discussion of the mechanisms by which this happens, the very fact that it can happen demonstrates the possibility of reversing the worst aspects of Alzheimer's. Thus memories and the working structures of the brain must remain largely intact until fairly late in the progression of the disease.

There is clearly a point in Alzheimer's, and other neurodegenerative diseases, beyond which the damage caused by the condition is irreversible. Neurons die, and in large enough numbers to destroy vast swathes of information held in the brain - the very foundation of who you are, and the vital components of systems needed to live a normal life. All is not gloom, however. Studies in past years have suggested that up to that point, much of the loss of function that accompanies Alzheimers is in principle reversible:

Some evidence suggests that the worst effects of Alzheimer's disease can be repaired - that memories are not destroyed, but rather become inaccessible.

Another recent study adds to this picture:

Amyloid-beta and tau protein deposits in the brain are characteristic features of Alzheimer disease. The effect on the hippocampus, the area of the brain that plays a central role in learning and memory, is particularly severe. However, it appears that the toxic effect of tau protein is largely eliminated when the corresponding tau gene is switched off.

Researchers from the Max Planck Research Unit for Structural Molecular Biology at DESY in Hamburg have succeeded in demonstrating that once the gene is deactivated, mice with a human tau gene, which previously presented symptoms of dementia, regain their ability to learn and remember, and that the synapses of the mice also reappear in part. The scientists are now testing active substances to prevent the formation of tau deposits in mice. This may help to reverse memory loss in the early stages of Alzheimer disease - in part, at least.

For yet another consideration of early to mid-stage Alzheimer's as a form of dynamic blockage of memory access, you might also look at the effects of some newer anti-inflammatory treatments:

The [study from 2008] documents a dramatic and unprecedented therapeutic effect in an Alzheimer's patient: improvement within minutes following delivery of perispinal etanercept, which is etanercept given by injection in the spine.

Putting aside a discussion of the mechanisms by which this happens, the very fact that it can happen demonstrates the possibility of reversing the worst aspects of Alzheimer's. Thus memories and the working structures of the brain must remain largely intact until fairly late in the progression of the disease.

A promising open access study: "Transplanting autologous renal progenitor cells (RPCs), (kidney stem cells derived from self-donors), into rat models with kidney damage from pyelonephritis - a type of urinary infection that has reached the kidney - has been found to improve kidney structure and function. ... Advancements in stem cell therapies and tissue engineering hold great promise for regenerative nephrology. Our RPC transplant study demonstrated benefits for pyelonephritis, a disease characterized by severe inflammation, renal function impairment and eventual scarring, and which remains a major cause of end-stage-renal disease worldwide. ... The researchers divided 27 rats into three groups, two of which were modeled with an induced pyelonephritis in their right kidneys, while the third group did not have induced disease. RPCs were obtained from the diseased animals' left kidneys and injected into the right kidney six weeks later. Two weeks after injection, tubular atrophy was reduced. After four weeks, fibrosis was reduced and after sixty days, right renal tissue integrity was 'significantly improved.' ... We propose that kidney augmentation was mainly due to functional tissue regeneration following cellular transplantation. Kidney-specific stem/progenitor cells might be the most appropriate candidates for transplantation because of their inherent organ-specific differentiation and their capacity to modulate tissue remodeling in chronic nephropathies. ... The researchers concluded that because renal fibrosis is a common and ultimate pathway leading to end-stage renal disease, amelioration of fibrosis might be of major clinical relevance."

Link: http://www.eurekalert.org/pub_releases/2011-02/ctco-sct021411.php

From the Telegraph: "India's first set of government-approved clinical trials of stem cells on patients with chronic obstructive lung disease, diabetes, liver cirrhosis and osteoarthritis are likely to begin in five cities in April this year. A Bangalore-based company, Stempeutics Research, has received approval from the country's drug regulatory agency to evaluate the efficacy of its stem cells on these four incurable diseases after safety assessments over the past year on patients with cardiovascular disease. The efficacy - Phase II - trials are likely to begin on small groups of volunteer patients offered the experimental treatment in collaborating hospitals in Bangalore, Kochi, Delhi, Mangalore and Manipal, a senior Stempeutics official said. Each volunteer patient will receive a dose of mesenchymal stem cells derived from the bone marrow of healthy persons. The stem cells, coaxed to proliferate in a broth of laboratory biochemicals, will be injected at the site of illness - the pancreas, the liver, the lungs, or the bone - where they are expected to stimulate resident stem cells and regenerate the damaged or lost tissue. While private and even government hospitals have in the past offered stem cell therapy to patients with intractable conditions, the proposal by Stempeutics is the first with formal approval from regulators for chronic obstructive pulmonary disease (COPD), diabetes, liver cirrhosis and osteoarthritis."

Link: http://www.telegraphindia.com/1110216/jsp/frontpage/story_13589821.jsp

The Science for Life Extension Foundation is a Russian organization consisting of advocates and aging researchers. They are similar to the SENS Foundation in that they undertake a mix of fundraising, directing research, organizing events, advocacy for longevity science, and publishing on potential methodologies to extend the healthy human life span. These two groups even share some members and advisors in common - it's a small world these days, after all, and aging research is not a large community to begin with. That is one of many things we like to see change over the next decade or two: if you want rapid progress, there need to be many researchers at work.

The Science for Life Extension Foundation has published a number of professional quality documents that can be downloaded in PDF format from their website. Unfortunately not all of them are available in English, and automated translation of PDFs remains somewhat hit and miss. I did want to direct your attention to one of the documents, however, which is entitled "25 Scientific Ideas of Life Extension." It is a very elegantly designed, very clear booklet aimed at investors. The PDF packages up a series of scientific research programs aimed at extending human life into compelling elevator pitches - but just saying that doesn't do it justice. It really is very well done indeed, and you should take a look:

I picked out one of the twenty-five that focuses on a research theme you might be familiar with, as I've mentioned it in the past. If you look back in the Fight Aging! archives, you can read more about Cuervo's work on autophagy and lysosomal receptors:

• A Little More On Preventing Decline in Liver Function With Age
• An Update on Cuervo's Autophagy Research

In experiments, livers in genetically modified mice 22 to 26 months old, the equivalent of octogenarians in human years, cleaned blood as efficiently as those in animals a quarter their age. By contrast, the livers of normal mice in a control group began to fail. ... While her paper does not show increased survival rates among the mice, le Couteur, who has advised her recently on the research, says Cuervo does have data on improved survival rates which she intends to publish.