The continued search for ways to more quickly determine differences in expected longevity between members of the same species finds a potential marker: "Xenobiotic metabolism has been proposed to play a role in modulating the rate of aging. Xenobiotic-metabolizing enzymes (XME) are expressed at higher levels in calorically restricted mice (CR) and in GH/IGF-I-deficient long-lived mutant mice. In this study, we show that many phase I XME genes are similarly upregulated in additional long-lived mouse models, including "crowded litter" (CL) mice, whose lifespan has been increased by food restriction limited to the first 3 weeks of life, and in mice treated with rapamycin. Induction in the CL mice lasts at least through 22 months of age, but induction by rapamycin is transient for many of the mRNAs. Cytochrome P450s, flavin monooxygenases, hydroxyacid oxidase, and metallothioneins were found to be significantly elevated in similar proportions in each of the models of delayed aging tested, whether these are based on mutation, diet, drug treatment, or transient early intervention. The same pattern of mRNA elevation can be induced by 2 weeks of treatment with tert-butylhydroquinone, an oxidative toxin known to active Nrf2-dependent target genes. These results suggest that elevation of phase I XMEs is a hallmark of long-lived mice and may facilitate screens for agents worth testing in intervention-based lifespan studies."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22693205

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Researchers here report on another way to tell old stem cells to get back to work on maintaining muscle tissue - though not one that has immediate application, as it requires removal of an important component of immune system function. Thus this is only promising if researchers can pick apart the different functions of this component and interfere only where it suppresses stem cell activity in muscle regeneration: "Wnt signaling plays critical roles in development of various organs and pathogenesis of many diseases, and augmented Wnt signaling has recently been implicated in mammalian aging and aging-related phenotypes. We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. ... Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption. Our findings therefore suggest the unexpected role of complement C1q in Wnt signal transduction and modulation of mammalian aging."

Link: http://www.cell.com/retrieve/pii/S0092867412005314

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Whole brain emulation is the topic for today: being able to run all of the processes of a brain on some form of computing machinery other than the evolved biological structures we presently possess. Considered in the long term this is an important line of research, as radical life extension will ultimately require moving away from flesh and into some more robust form of machinery in order to better manage the risk of fatal accidents. 'Ultimately' here is a long way into the future, centuries or more, long after we have solved the basic problems of repairing our aging biology so as to attain continual youth. Some people will be satisfied with copying themselves from their biological substrate into a machine substrate and letting that machine copy continue on, but that seems to me little more than an expensive form of procreation - continuation of the self requires a slow transformation of the original, not a quick cut and paste of data to a new computing device. But this is an old and often rehashed argument between identity as pattern and identity as continuity.

Here are some past posts on whole brain emulation if you'd like to do some background reading:

• A Preliminary Roadmap to Whole Brain Emulation
• The Age of Artificial Brains

Regardless of how people decide to use the ability to host a conscious individual somewhere other than a human brain, the technologies of whole brain emulation will have to be built. They are a precursor to any program of replacing the brain's present biological machinery with something better. From where I stand, brain emulation is also the most plausible path to true artificial intelligence, which at this time looks far more likely to arise from attempts to duplicate and then improve on the operation of human brains than from efforts to improve expert systems of varying sorts.

Reasonable people differ on this, of course, as even a brief survey of publications on artificial intelligence will tell you.

If you find this topic interesting, you might look at the latest issue of the International Journal of Machine Consciousness, featuring many of the usual suspects from the transhumanist community - folk who have been putting in time on AI and molecular nanotechnology research for some years. A couple of the more intriguing items:

Non-Destructive Whole-Brain Monitoring Using Nanorobots: Neural Electrical Data Rate Requirements

Neuronanorobotics, a promising future medical technology, may provide the ultimate tool for achieving comprehensive non-destructive real-time in vivo monitoring of the many information channels in the human brain. This paper focuses on the electrical information channel and employs a novel electrophysiological approach to estimate the data rate requirements, calculated to be (5.52 ± 1.13) × 10^16 bits/sec in an entire living human brain, for acquiring, transmitting, and storing single-neuron electrical information using medical nanorobots, corresponding to an estimated synaptic-processed spike rate of (4.31 ± 0.86) × 10^15 spikes/sec.

Why Uploading Will Not Work, or, the Ghosts Haunting Transhumanism

Transhumanists tend to have a commitment to materialism and naturalism but nonetheless pursue goals traditionally associated with religious ideologies, such as the quest for immortality. Some hope to achieve immortality through the application of a technology whereby the brain is scanned and the person "uploaded" to a computer. This process is typically described as "transferring" one's mind to a computer.

I argue that, while the technology may be feasible, uploading will not succeed because it in fact does not "transfer" a mind at all and will not preserve personal identity. Transhumanist hopes for such transfer ironically rely on treating the mind dualistically - and inconsistently with materialism - as the functional equivalent of a soul, as is evidenced by a carefully examination of the language used to describe and defend uploading. In this sense, transhumanist thought unwittingly contains remnants of dualistic and religious concepts.

A Framework for Approaches to Transfer of a Mind's Substrate

I outline some recent developments in the field of neural prosthesis concerning functional replacement of brain parts. Noting that functional replacement of brain parts could conceivably lead to a form of "mind-substrate transfer" (defined herein), I briefly review other proposed approaches to mind-substrate transfer then I propose a framework in which to place these approaches, classifying them along two axes: top-down versus bottom-up, and on-line versus off-line; I outline a further hypothetical approach suggested by this framework. I argue that underlying technological questions about mind-substrate transfer, there is a fundamental question which concerns our beliefs about continuity of identity.

On this last topic, present developments in neural prosthetics are well worth the time taken to investigate. Being able to replace some lesser pieces of the brain in the event of damage is on the verge of being a going concern - sometime within the next twenty years there will be a fair number of people walking around with implanted medical devices in their brains. Those devices will replace or augment the function of one or more component parts of the brain, allowing these patients to live where they would otherwise have died or suffered a lower quality of life. This is the start of the next wave of mapping the physical structure of the brain to its function, and that field of research will expand and accelerate just like all other areas of medicine, driven by the ongoing biotechnology revolution.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Via EurekAlert!: "Regenerative medicine, or the use of specially grown tissues and cells to treat injuries and diseases, has been successful in treating disorders of a number of organs, including heart, pancreas, and cartilage. However, efforts to treat disorders of the corneal endothelium, a single cell layer on the inner surface of the cornea, with regenerative techniques have been less effective. Now, a group of scientists has developed a method that enhances the adhesion of injected corneal endothelial cells (CECs), allowing for successful corneal transplantation to repair pathological dysfunctions. ... Previous studies demonstrated that Rho-associated kinase (ROCK) signaling interferes with adhesion. We found that transplanting cultivated CECs in combination with a low-molecular weight compound that inhibits ROCK (ROCK inhibitor Y-27632), successfully achieved the recovery of corneal transparency. ... Using rabbit cells, researchers cultivated CECs in the lab and injected them into the anterior chamber of rabbit eyes with damaged corneal endothelia. Based on the recovery of the corneal endothelial function, they found that when the cultivated cells were injected along with Y-27632, the rabbit corneas regained complete transparency 48 hours after injection. ... Since rabbit CECs are highly prolific in vivo, the scientists performed another round of experiments with monkey CECs, which are more similar to those in humans. The transplantation of CECs in these primates also achieved the recovery of long-term corneal transparency with a monolayer of hexagonal cells, suggesting that cell adhesion modified by ROCK inhibitor may be an effective treatment for human corneal endothelial disorders."

Link: http://www.eurekalert.org/pub_releases/2012-06/ehs-rcm061112.php

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

From the BBC: "A 10-year-old girl has had a major blood vessel in her body replaced with one grown with her own stem cells. ... A vein was taken from a dead man, stripped of its own cells and then bathed in stem cells from the girl, according to a study published in the Lancet. Surgeons said there was a "striking" improvement in her quality of life. This is the latest is a series of body parts grown, or engineered, to match the tissue of the patient. Last year, scientists created a synthetic windpipe and then coated it with a patient's stem cells. ... In this case, other options such as using artificial grafts to bypass the blockage, had failed. ... It used a process known as "decellularisation". It starts with a donor vein which is then effectively put through a washing machine in which repeated cycles of enzymes and detergents break down and wash away the person's cells. It leaves behind a scaffold. This is then bathed in stem cells from the 10-year-old's bone marrow. The end product is a vein made from the girl's own cells. ... The young girl was spared the trauma of having veins harvested from the deep neck or leg with the associated risk of lower limb disorders."

Link: http://www.bbc.co.uk/news/health-18428889

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Sarcopenia is the umbrella name for the progressive loss of muscle mass and strength with age - which may turn out to cover a range of separate mechanisms. The progression of sarcopenia appears to be reduced by the practice of calorie restriction, and might also be slowed by a range of possible therapies such as exercise and dietary leucine supplementation or targeting the myostatin gene and its protein product. Levels of inflammation also show up as a possible contributing factor - more chronic inflammation is a bad thing across the board.

Here is an open access paper that touches on much of what the mainstream research community is investigating when it comes to sarcopenia.

Sarcopenia, the age-related loss of skeletal muscle, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, and an increased risk of fall-related injuries. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, numerous targets exist for drug discovery. In this paper, we summarize the current understanding of the endocrine contribution to sarcopenia and provide an update on hormonal intervention to try to improve endocrine defects. Myostatin inhibition seems to be the most interesting strategy for attenuating sarcopenia other than resistance training with amino acid supplementation.

...

Several researchers have investigated the effect of inhibiting myostatin to counteract sarcopenia using animals. Lebrasseur et al. found that treatment with a mouse chimera of antihuman myostatin antibody (24?mg/Kg, 4 weeks), a drug for inhibiting myostatin, elicited a significant increase in muscle mass and in running performance ... More recently, Murphy et al. showed, by way of once weekly injections, that a lower dose of this anti-human myostatin antibody (10?mg/Kg) significantly increased the fiber cross-sectional area (by 12%) and in situ muscle force (by 35%) of aged mice (21?mo old). These findings highlight the therapeutic potential of antibody-directed myostatin inhibition for sarcopenia by inhibiting protein degradation.

Work on myostatin therapies is one of the topics worthy of greater attention here, as this seems like it would be a generally beneficial gene therapy for everyone - something that, given a good safety profile, most people would want to undergo earlier in life. The first step towards widespread availability for this sort of human enhancement is to develop the necessary medical technology in in the first place, of course, and these days that's only going to happen in the service of treating a specific medical condition.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

An article from Cryonics Magazine: "Cryopreserved patients must be cared for for at least decades and some anticipate centuries. During this time, some caretaker organization must look after the patients. This involves paying the rent and utilities, replacing liquid nitrogen, maintaining and replacing dewars, hiring and paying staff, and a host of other activities that must be done reliably and economically. The usual arrangement is for the patient to make a lump sum payment into a common fund, the interest from which will then pay the expenses of maintaining a group of patients in cryopreservation for whatever period of time might be required. At Alcor, the lump sum payment is made into the PCT (Patient Care Trust), and the payment made by each patient is the 'PCT allocation,' taken from the total payment made by the patient at the time of cryopreservation. Determining the appropriate amount of the PCT allocation can raise questions whose answers are not always obvious and can sometimes be quite dilemmatic. ... Contractual and financial arrangements must usually be in place before a patient can be cryopreserved. The financial arrangements involve payment for both the up-front procedures and long term care. These payments are usually bundled, and at Alcor the total amount of money that is required is called the 'funding minimum'. The funding minimum is usually paid with life insurance. ... The focus of this article is on the lump sum payment made into the common fund from the funding minimum by the patient at the time of the patient's cryopreservation."

Link: http://www.alcor.org/magazine/2012/06/11/the-allocation-of-long-term-care-costs-at-alcor/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

The build up of senescent cells is one of the contributing causes of aging, and is partially due to the progressive failure of the immune system to destroy these cells as they crop up. Many of the changes that come with aging accelerate as they progress, and this piece provides one example as to why this is the case; for senescent cells, the more you have the faster they accumulate: "Cells may become senescent in an effort to protect the body such as when tumor suppressor genes shut down division to prevent cancer. However other sorts of damage may lead cells to stop dividing as well. A pivotal study last year showed elegantly using a trangenic approach that if senescent cells were regularly cleared from the body of mice, signs of aging in many tissues were dramatically reduced. The explanation for this result was that somehow senescent cells were damaging nearby cells, perhaps by excreting toxic materials. ... A newly published study [proves] or the first time that senescent cells do indeed damage nearby cells causing them to become senescent too. It also shows this occurs through direct cell to cell contact and resultant spread of reactive oxygen species. Furthermore it shows evidence this process occurs in the living organism as clusters of cells bearing senescent makers are found in mice livers. Clearly the next and important step for helping to reduce aging in humans is developing a safe and effective method presumably using a pharmacological agent in which senescent cells can be removed from the body."

Link: http://extremelongevity.net/2012/06/11/study-proves-senescent-cells-cause-nearby-cells-to-become-senescent/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

DNA methylation is a part of epigenetics, one of the mechanisms by which protein machinery produced from DNA creates feedback loops to change the production levels of many different proteins. Genes are decorated with a continually altering array of chemical signals, changing with circumstances and environment. The cell nucleus is a factory, DNA the component blueprints, and DNA methylation one portion of the chaotic parts order list: from moment to moment, how much to make of each piece of protein machinery encoded in the genome.

DNA methylation changes with age, location within the body, and type of cell, a fuzzy and very complicated pattern of decorated genes. Some of the myriad changes are sufficiently similar from person to person to be a possible method to determine age quite accurately. Others are known to reflect the degree to which a person becomes frail with age. Many more are not understood at all, or may be largely random.

A great many debates within aging science revolve around the difference between cause and consequence - and so too with DNA methylation. Is it a part of the expected attempts by the body to adapt to increasing levels of cellular damage caused by aging, or is at least some alteration in DNA methylation a form of damage in and of itself? Good arguments can be made either way, but for my money I'd be surprised to see significant levels of epigenetic changes that were anything other than the results of underlying damage and evolutionary adaptations that try (and ultimately fail) to cope with that damage.

This debate is significant, of course, because of how it directs research and development funding. Will scientists try to patch over the root causes of aging by altering its secondary effects - inevitably doomed to be expensive and comparatively ineffective - or will they work to repair the true causes, and thereby remove the secondary effects for free? There's been a great deal too much work on patching over the cracks in the medicine of past decades, and in this age of biotechnology it seems a sin to continue that way when we don't have to.

In any case, here is news of more recent work on DNA methylation that has been doing the rounds:

DNA Switches Discovered to Decline Significantly with Age

An important element of the DNA is what is known as the epigenome. This refers to the pattern of added chemical tags on the DNA called methyl groups. These tags may alter the expression of genes near or on which they reside. Usually they turn off expression of the gene on which they reside.

...

A team of researchers decoded and compared the entire epigenome from blood cells in a neonate, a 26 year old, and a 103 year old. The results were striking. The researchers discovered that as the cells aged, the epigenome changed dramatically. They found 80% of all cysteine residues were methylated in the newborn compared to just 73% of them in the centenarian. A 26 year old subject had 78% of them methylated. They also found almost 18,000 locations in the genome where methylation varied the most. About one third of those regions occurred in genes linked to increase risk of cancer. Mostly aging involved loss of methyl groups.

Why do we age? Genomes of baby and 103-year-old may offer clue

The researchers analyzed the genome of the baby's white blood cells (obtained from cord blood). They found more than 16 million spots where methyl groups had been attached to the baby's DNA. But when they did the same thing with the old man's DNA (obtained from his white blood cells), they found nearly 500,000 fewer sites with methyl groups attached. The sites weren't as densely methylated either.

The scientists got a similar result when they looked in a larger group of 19 Caucasian newborns and 19 Caucasian nonogarians (average age 92.6). And they found an intermediate level of methylation when they examined the white-blood-cell DNA of 19 middle-aged people (average age about 60).

The scientists went on to take a closer look at a few specific genes where they'd spotted changes in methylation in their samples and found that the activity of the genes that had been depleted in methyl groups was, indeed, changed. And they noted that some of the genes - such as two called Sirtuin 5 and Sirtuin 7 - are thought from other studies to be involved in the biology of aging.

As I said above, I don't think epigenetic changes have much to say about why we age, as they are not a fundamental change. They may encode many of the details of how we age, however - ways in which low-level damage translates into characteristic changes in the way that cells, systems, and organs operate. This may be very valuable, but equally it doesn't change the basic goal, which is to repair the fundamental forms of damage that drive aging.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm