Fight Aging! Newsletter, March 24th 2014

March 24th 2014

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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  • A Little Cryonics History, Lest We Forget
  • The Golgi Apparatus in Alzheimer's Disease
  • Manipulation of Lamins Can Extend Life as Well as Shorten It
  • A Speculative and Probably Incorrect Paper on Alzheimer's Disease as a Consequence of Modern Painkillers
  • Survival and Longevity: Why Bother?
  • Latest Headlines from Fight Aging!
    • Failing to Extend Life Via Altered Levels of Membrane Fatty Acid Unsaturation
    • ECP Knockdown Extends Life in Flies, Probably via AMPK
    • Examining Mitochondrial DNA Damage With Aging in Human Tissues
    • Axon Debris and Declining Nerve Regeneration With Age
    • Muscle Stem Cells Aid in Repair of Nerve Damage
    • More Modeling of the Grandmother Hypothesis
    • Betting Against Longevity, and Concerned About It
    • Lower Resting Metabolic Rate Correlates With a Lower Risk of Age-Related Conditions and Impairments
    • Investigating Osteoblast Deficiencies in Aspects of Osteopenia
    • REST and Alzheimer's Disease


Approximately 150,000 people die every day, two thirds of those due to the effects of aging. As a result their individuality, their minds, the pattern of data encoded in the fine structure of the cells of the brain, is destroyed and lost to oblivion. They are gone, irrevocably and irreversibly. But it doesn't have to be this way: the technologies exist to preserve most of these people at death, and store their brains - their minds, their selves - for a future in which they can be restored to life in a new body. Yet they are not used. The small and largely unappreciated field of cryonics offers the option of low-temperature preservation to await a future of profoundly capable medical technology, but barely 200 people have taken up that offer over the past four decades.

Cryonics as an industry presently consists of two established professional non-profit organizations, both decades old, a handful of supporting companies and groups offering various services other than preservation, and a few younger organizations established in recent years. The broader cryonics community seems perpetually on the cusp between young industry and growing industry: it has never managed to break out from the early niche. A great deal of ink has been spilled and many theories proposed as to why this is the case - perhaps it is a subset of the broader disinterest in living longer lives that is displayed by the public at large.

So instead of living in a rational world, in which as many people as possible have the chance to be rescued from oblivion through a competitive, large-scale cryonics industry, we live in a world in which the masses march knowingly to death and destruction, near every last one of them shunning the few paths that might prevent that end. Cryonics, research into reversal of aging, and so forth: these are greeted with yawning disinterest or mockery by the population at large.

Cryonics has become more accepted, and great strides have been made in growing support for rejuvenation research in the past ten years, I should mention. But we have incremented the counter just a few notches, and there are another hundred left to go if we want to see a research community the size of the cancer or stem cell establishment working away to produce a halt to degenerative aging. Meanwhile people still die of aging, and cryonics is the only presently available option other than the grave.

Every industry has its early disasters, and cryonics is no exception: these largely happened in the late 1960s and 1970s, when amateurs promised more than they could afford and could deliver, and as a result preserved individuals were lost. We should not forget, because when you forget these unpleasant histories you stop striving to be better. The only way to deliver good service over the long term is to adopt the rules and rigor of professionalism, just the same as in any business, whether for profit or otherwise. The established cryonics providers of today remain small organizations, but they are a world removed from the early years of amateur groups and comparatively poor preservation methods. Here is a look back:

Cryonics pioneer still hopeful

The history of any radical idea has its heroes and its villains. In cryonics, Bob Nelson has been both. He was among the first to embrace the notion that a person could be eased into a deep freeze at the moment of death, preserved indefinitely in a thermos-like container of liquid-nitrogen, and then brought back to life when advances in medicine and technology allow it.

On Jan. 12, 1967, as president of the Cryonics Society of California, he helped freeze the first man, a 73-year-old retired psychology professor from Glendale who had cancer. That pioneering experiment turned Nelson into a media sensation - TV shows, newspaper interviews, magazine covers. Twelve years later, sensation gave way to scandal. Nine bodies Nelson was preserving in a cemetery vault in Chatsworth thawed, halting their journey to a better tomorrow. Some of the relatives sued Nelson and a colleague and won $800,000.

He disappeared from public view, changed his name, and settled into what he was before cryonics captured his imagination: a TV repairman. About 20 years ago, he moved to Oceanside. "I swore I would never ever even say the word cryonics again," he said.

Mike Perry, a cryonics historian who is a case services manager for Alcor, said Nelson deserves credit for helping to freeze the first person, but the "horrific" failure at Chatsworth still "burns in people's minds" as a cautionary tale. "We have to be sure there is adequate funding before committing ourselves to the demanding task of long-term maintenance of persons in cryogenic storage," Perry said.

To be clear, a preserved individual is still an individual. They still have the potential to return in the future. Nelson offered a rescue from an otherwise fatal situation, failed to carry through successfully, and was judged and still is judged on that. That most people and the legal system consider cryopreserved individuals to in effect no longer be people, nor to have rights, nor a voice beyond the murky law of wills and posthumous trusts, is somewhat beside the point.


There are a great many exceedingly complex and still comparatively poorly understood structures inside our cells. If you're even passingly familiar with the varied roles of mitochondrial damage or protein misfolding or the the decline of cellular housekeeping processes such as autophagy in aging, then the Golgi apparatus certainly has the look of a thing that should be more important in aging than seems to be the case. You'll find no mention of it in the Fight Aging! archives prior to today:

Cells synthesize a large number of different macromolecules. The Golgi apparatus is integral in modifying, sorting, and packaging these macromolecules for cell secretion (exocytosis) or use within the cell. It primarily modifies proteins delivered from the rough endoplasmic reticulum but is also involved in the transport of lipids around the cell, and the creation of lysosomes. In this respect it can be thought of as similar to a post office; it packages and labels items which it then sends to different parts of the cell.

Where the Golig apparatus is implicated in aging, it is in the context of Alzheimer's disease. In the brain cells of Alzheimer's patients the Golgi apparatus seems to fall apart, and researchers here suggest that this is an important step in the progression of pathological effects at the biochemical level. They identified one of the mechanisms by which the progression of Alzheimer's is sabotaging the Golgi structures, blocked it, and saw a consequent reduction in levels of the characteristic harmful amyloid beta associated with Alzheimer's disease. That is somewhat promising, even if only accomplished in cells rather than laboratory animals:

U-M scientists slow development of Alzheimer's trademark cell-killing plaques

University of Michigan researchers have learned how to fix a cellular structure called the Golgi that mysteriously becomes fragmented in all Alzheimer's patients and appears to be a major cause of the disease. They say that understanding this mechanism helps decode amyloid plaque formation in the brains of Alzheimer's patients - plaque that kills cells and contributes to memory loss and other Alzheimer's symptoms.

The researchers discovered the molecular process behind Golgi fragmentation, and also developed two techniques to 'rescue' the Golgi structure. "We plan to use this as a strategy to delay the disease development. We have a better understanding of why plaque forms fast in Alzheimer's and found a way to slow down plaque formation."

Researchers found that the accumulation of the Abeta peptide - the primary culprit in forming plaques that kill cells in Alzheimer's brains - triggers Golgi fragmentation by activating an enzyme called cdk5 that modifies Golgi structural proteins such as GRASP65. [The researchers] rescued the Golgi structure in two ways: they either inhibited cdk5 or expressed a mutant of GRASP65 that cannot be modified by cdk5. Both rescue measures decreased the harmful Abeta secretion by about 80 percent. The next step is to see if Golgi fragmentation can be delayed or reversed in mice.

Some research in the Alzheimer's field suggests that amyloid levels in the brain are fairly dynamic, and thus Alzheimer's may well be a progressive failure of processes that work to clear out harmful amyloid, not a slow accumulation of unwanted compounds. If that is the case, a way to reduce the pace of creation might be enough to tip things back over into a comparatively healthy state. The only fix in the long term, however, is to identify and eliminate the root causes of the condition, whatever they might turn out to be.


Hutchinson‐Gilford progeria syndrome (HGPS, or just plain progeria) is perhaps the best known of the rare but striking accelerated aging conditions caused by genetic mutation. These are not in fact accelerated aging, despite the apparent outcome, but rather DNA repair deficiencies. The water is always muddy when talking about damage and aging, however. Aging is just an accumulation of damage, and progeria is perhaps best thought of as an ordinarily fairly unimportant aspect of aging run amok to create a great deal of damage and dysfunction in cells and tissues.

Over the past decade or so researchers have come to a good understanding of the cause and mechanisms of progeria. An otherwise minor mutation in the LMNA gene leads to the generation of broken forms of a vital cellular structural protein, lamin A, and things go downhill from there: a progeria patient's cells are greatly malformed and perform poorly at the most crucial of their tasks. Interestingly, dysfunctional forms of this protein show up in small but increasing amounts over the course of normal aging, and are thought to be just as harmful - but on a much smaller scale, producing a much smaller detrimental effect. This has yet to be proven conclusively or quantified in any useful way, however.

To draw a perhaps overly simplistic analogy, if aging is running low on oil in your engine, then progeria is having a hole in your oil tank. They are similar in the sense that the end result is similar, and they share commonalities in their progression, but the root cause is completely different - and in the case of the hole in the tank, the unfortunate end result arrives a lot more rapidly. Knowing how to fix holes in oil tanks does nothing for efforts to make oil use more efficient, and it isn't of much help when it comes to repair efforts for the vast majority of engine-owners as they won't suffer oil tank holes.

It is an open question as to the degree to which small amounts of malformed lamin A contribute to degenerative aging, or even whether it is a cause or secondary effect of other forms of cellular and molecular damage that accumulate over time. The research linked below doesn't answer that question, but it certainly makes the whole area of lamin studies much more interesting - as is always the case if you can demonstrate extension of life in mice:

Antagonistic functions of LMNA isoforms in energy expenditure and lifespan

Alternative RNA processing of LMNA pre‐mRNA produces three main protein isoforms, that is, lamin A, progerin, and lamin C. De novo mutations that favor the expression of progerin over lamin A lead to Hutchinson‐Gilford progeria syndrome (HGPS), providing support for the involvement of LMNA processing in pathological aging.

Lamin C expression is mutually exclusive with the splicing of lamin A and progerin isoforms and occurs by alternative polyadenylation. Here, we investigate the function of lamin C in aging and metabolism using mice that express only this isoform. Intriguingly, these mice live longer, have decreased energy metabolism, increased weight gain, and reduced respiration. Our results demonstrate that LMNA encodes functionally distinct isoforms that have opposing effects on energy metabolism and lifespan in mammals.

It isn't at all clear as to how exactly the different lamins are involved in generating or avoiding this extension of life, given the resulting alterations in all sorts of interdependent aspects of metabolism, but I'm sure that other researchers will look in on this in the years ahead.


Once you know enough of the basics in a field to get by as a layperson, you'll find that scientific literature is far removed from being dry and uncontroversial. There are always heretics and novel positions being advanced - most of them wrong, but all new fields and new directions start with a few heretics, and the mainstream is consistently overturned with time, to be replaced with the new consensus. Distinguishing a good speculative hypothesis from a work of overreaching fancy can be a challenge wherever you stand in the hierarchy of knowledge, and the good-looking fallacies far outnumber the seeds of tomorrow's scientific mainstream. This is why few researchers bother to spend any time on reviewing this sort of thing when there are so very many other demands on their time.

One of the SENS Research Foundation folk turned up the open access paper linked below in the course of ongoing reviews of scientific literature relevant to aging, and thought it heretical enough to share as an item of interest - as a curio well outside the current consensus, not as anything to be acted on. It makes for a good read, and is well-researched, but I think that ultimately the points being made here can be explained away by the coincidence of development of medical technology, increasing longevity, and increasing wealth. When it comes down to the biochemistry, the dots aren't really joined well enough to be very compelling.

So I offer this as an example of the fact that if you go digging around, you'll find very interesting papers that are well-researched, highly speculative, and probably wrong. The author of this paper has been advancing his theory for more than a decade, evidently without gathering much support. That is all part and parcel of the scientific process:

The Alzheimer Pandemic: Is Paracetamol to Blame?

Historical Background:

The clinical recognition of a form of dementia closely resembling Alzheimer's disease dates from around 1800. The role of analgesics derived from coal-tar in the spread of the pandemic is traced in terms of the introduction of phenacetin (PN) in 1887; its nephrotoxicity; the observation of lesions characteristic of the disease by Fischer and Alzheimer; the discovery of paracetamol (PA) as the major metabolite of PN; the linking of kidney injury and dementia with high PN usage; and the failure of PN replacement by PA to halt and reverse the exponential, inexorable rise in the incidence of Alzheimer-type dementia. Fischer observed his first case before Alzheimer; it is proposed to rename the syndrome Fischer-Alzheimer disease (F-AD).

Disease development:

PA-metabolising enzymes are localised in the synaptic areas of the frontal cortex and hippocampus, where F-AD lesions arise. The initiating chemical lesions in liver poisoning comprise covalent binding of a highly reactive product of PA metabolism to proteins; similar events are believed to occur in brain, where alterations in the antigenic profiles of cerebral proteins activate the microglia. β-Amyloid forms, and, like PA itself, induces nitric oxide synthase.


F-AD is primarily a man-made condition with PA as its principal risk factor.

The ending line there is something of a bold conclusion, and as I noted above I don't think it stands too well against Occam's razor. It is simpler to point to rising wealth driving the sedentary, high-calorie lifestyle that greatly raises the risk of suffering age-related diseases such as Alzheimer's, and note that this coincides with advances in medical technology that allow for more reliable identification of the condition, progress in other technologies that improve record-keeping and reliability in medicine, and the concurrent trend in rising life spans such that more people survive to ages in which neurodegenerative conditions become a significant risk.

I still suggest you read the paper, as you'll find that a great deal of interesting historical data is referenced therein. You'll probably learn some things that you didn't know about the history of painkillers, for example.


Live or die: why does it matter to you? Why strive, why bother? The first stoics long ago pointed out that dead is dead; fear dying by all means, but do not fear being nothing. Or, from Epicurus, we have the epitaph "I was not, I was, I am not, I care not."

I recently engaged in a passing conversation with a young lady on the topic of the progress of medical science towards enhanced longevity. She recognized that medicine was improving but chose to do nothing to improve the odds for her own future - to be a person who will take advantage of future medical advances when they arrive, but who is content to live whatever life and life span falls out of chance and the actions of others. One wonders if the many people who think and act this way have an accurate picture of the suffering involved in being aged, frail, and decrepit, but it is a common viewpoint. These folk head towards death in the distance, but feel no urgency, no urge to do anything but die alongside the rest of the herd. Yet when the damage of aging presses its claws in, these are the very same people who, decades from now, will reach out for the best medical help available. It is a puzzle to me, the absolute contradiction of individuals who intricately plan out finances and life courses for the decades ahead in all matters except helping to build the better medicine that will ease their future. Their view of technological progress is passive, that it is something that just happens, perhaps.

But why be different, why bother? Why survive at all, given the stoic view? Why live? Why put in all this effort for a shot at a life span far longer than the measly four score or so years that is all that most of us would get in the environment of today's medical technology? That is a question with no answer but the one you fill in yourself, alongside the meaning of life and the laundry list of goals you feel you are here to achieve. It is self-determination all the way down.

In the case of rejuvenation research, there are obvious and compelling reasons to work on technologies to halt and reverse degenerative aging even absent a will to avert death. Rejuvenation treatments are the only long-term reliable solution to prevent the great suffering, pain, and cost that comes with aging while still alive. Preventing the breakdown of the body is a worthy, useful, and rational goal regardless of your position today on when you'd like to die. Many young people express the desire to die on the same timescale as their parents, but few are ready to volunteer for heart disease, chronic pain, cancer, and Alzheimer's disease if the question is put to them.

Cryonics and plastination, the preservation of the brain and the mind it contains against a better-equipped future in which restoration is a possibility, has a different dynamic. Because euthanasia is illegal in much of the world - a squalid state of affairs, in which disinterested bureaucrats force you into an undignified and horrible end simply because they can - cryonics cannot be used to bypass the suffering of aging. Instead the motivation here must be survival, pure and simple. The desire to live and act and see tomorrow's news.

Here's a post on this topic from one of the folk involved in the Brain Preservation Foundation, a group that favors plastination as an approach but runs a technology-agnostic research prize for the best contending approaches, presently vitrification and plastination. It is a reminder that there are as many views on survival as there are people willing to survive:

Brain Preservation: Why Bother? Getting to the Zen of Life

This talk explores the "Why Bother?" or Zen of Mortality perspective, which I think is the main reason that most folks, and particularly secular folks, don't yet see the value of [survival via plastination]. While I acknowledge the validity and great value of the Zen of Mortality perspective, and I used to hold it myself, I think there's an even more exciting and valuable perspective, the Zen of Life, waiting patiently for all of us who are ready to embrace it.

People who know how redundant the majority of their own memes are in culture, including most of the aspects of their individual self, are often very Zen (accepting, calm, serene) about dying. Today, in surveys done by David Ewing Duncan only 1% of people in the US, roughly 3 million of us, are interested in living beyond our biological death. This percentage may be even smaller in other developed countries, and particularly in the developing world. Certainly our unique religious and cultural beliefs play a role, but I think the main reason this percentage is so small is this strong Zen of Mortality, in almost all of us who think about this issue. Most of us know, in our gut, that our individual lives really don't "need" to be preserved, and are quite similar to those others around us who will live on. So why bother?

Let me now propose another Zen state, emerging now in a few places in our society, that is even more productive and enlightening than being comfortable with death. Let's call it the Zen of Life. There's something unique about Life as a process, that causes it to continually grow, learn, progress, and even accelerate at the leading edge of change. Transhumanists tend to focus on this latter process of accelerating change, and of transcending our prior limits, of continually being able to rejuvenate, grow, and learn. Understanding and imitating Life, in our thinking and practice, is even more interesting and rewarding for us than understanding and imitating Mortality. We can accept the Zen of Mortality, if that's the hand we're dealt. But if we are industrious, and lucky, we may turn ourselves into a continually improving and renewing system as well. That is the Zen of Life.

Let me now propose a vision. I believe having the option of affordable brain preservation at death, even if far less than 1% of us exercise this option, will nevertheless powerfully shift all societies where the option exists. We can imagine that these major positive social changes would happen at the moment social adoption reaches a significant minority (say, 100,000 preserved), regardless of when or how much mental information is eventually uploaded from preserved brains into computers in the future. Everyone would begin to know someone who had made the brain preservation choice. Conversations and values would start to shift now, as a result.


Monday, March 17, 2014

The membrane pacemaker hypothesis suggests that composition of cell membranes, especially those of mitochondria, is an important determinant of longevity differences between species - and possibly between individuals within a species as well. One specific proposed mechanism is the degree to which membranes contain unsaturated fatty acids, as these are more vulnerable to oxidative damage. Oxidative damage is connected to aging, but its role is subtle and complex: look back in the archives for an outline of the mitochondrial free radical theory of aging, for example, in which oxidative damage inside cells is only the initiator for a long chain of consequences.

Here researchers make an attempt to demonstrate the relevance of the membrane pacemaker hypothesis by running a life span study in mice wherein membrane unsaturated fatty acid levels are lowered. They achieve the expected results in mouse biochemistry, changes that look a lot like slowing of aging, but without any resulting extension of life - an outcome that they blame on side-effects of the method used:

The membrane fatty acid unsaturation hypothesis of aging and longevity is experimentally tested for the first time in mammals. Lifelong treatment of mice with the β1-blocker atenolol increased the amount of the extracellular-signal-regulated kinase signaling protein and successfully decreased one of the two traits appropriately correlating with animal longevity, the membrane fatty acid unsaturation degree of cardiac and skeletal muscle mitochondria, changing their lipid profile toward that present in much more longer-lived mammals.

The atenolol treatment also lowered visceral adiposity (by 24%), decreased mitochondrial protein oxidative, glycoxidative, and lipoxidative damage in both organs, and lowered oxidative damage in heart mitochondrial DNA. Atenolol also improved various immune (chemotaxis and natural killer activities) and behavioral functions (equilibrium, motor coordination, and muscular vigor). It also totally or partially prevented the aging-related detrimental changes observed in mitochondrial membrane unsaturation, protein oxidative modifications, and immune and behavioral functions, without changing longevity.

Side effects of the drug could have masked a likely lowering of the endogenous aging rate induced by the decrease in membrane fatty acid unsaturation. We conclude that it is atenolol that failed to increase longevity, and likely not the decrease in membrane unsaturation induced by the drug. The lack of modification of total body and organ weights (except for a decrease in kidney weight) and the absence of detection of variations in food intake indicate that the many observed beneficial effects of atenolol are not due to caloric restriction.

Monday, March 17, 2014

Too many ways to modestly slow aging in lower animals are being discovered nowadays to mention them all. These methods generally involve altering levels of one or more proteins, and then observing the resulting effects on metabolism and life span. As knowledge of the various pathways and mechanisms involved expands, it is becoming clear that most interventions discovered over the past two decades are linked to one another, being just different points of influence in the same larger set of mechanisms. So it isn't unusual at all for a novel method of life extension in laboratory animals to be connected to other, previously discovered methods, and that is the case here:

Inhibition of translation by mutations of a growing number of genes involved in protein synthesis could extend healthy lifespan in yeast, worm, fly and mouse as well. These genes vary from translation initiation factors to structural components of ribosomes and ribosomal RNA processing factors.

Eukaryotic initiation factor 5 C-terminal domain containing protein (ECP) is a novel ribosome associated protein. Previous data supports the involvement of this gene in long term memory formation and exon guidance in Drosophila probably through its still unconfirmed functions in protein synthesis. However, the exact molecular function of ECP is still largely unknown.

Our findings here show that fly lifespan could be significantly extended in ECP RNAi flies. Meanwhile, the locomotion ability of elder ECP RNAi flies was also improved remarkably. Further studies revealed an increase of mitochondria Complex IV activity in these ECP RNAi flies. A decrease of AKT and S6K phosphorylation level in contrast to an increase of AMPK phosphorylation level could also be detected in these flies. Together, these findings support a positive effect of ECP on longevity and delaying age-related impairment in locomotor behavior probably through activation of AMPK and enhancement of mitochondrial function via insulin/IGF-1 and TOR pathway.

Tuesday, March 18, 2014

We age in part because mitochondrial DNA accumulates mutations, probably via oxidative damage. Mitochondria exist as bacteria-like self-replicating herds within our cells, and mitochondrial function is essential to cellular processes. Mitochondria have their own DNA, distinct from that in the cell nucleus. This DNA is the blueprint for a number of essential portions of protein machinery used within mitochondria: severe mutations such as deletions can remove the ability of a particular mitochondrion to maintain itself and continue to operate correctly. Cellular quality control should destroy all such damaged mitochondria, but unfortunately some damage can cause forms of dysfunction that evade these quality control processes. This ultimately leads to cells overtaken by clones of a dysfunctional mitochondria, and which themselves become dysfunctional as a result, harming surrounding tissues.

Possible approaches to remove this contribution to degenerative aging include periodic mitochondrial DNA repair or replacement, and the SENS method of adding backup copies of the relevant genes to the cell nucleus.

Here is an example of research that supports this view, in which researchers examine the prevalence of mitochondrial DNA mutations with advancing age in human brain tissue, showing that deletion mutations increase significantly with age:

Mitochondria are unique among animal organelles in that they contain their own multi-copy genome (mtDNA). For the past 20 years it has been known that tissues like brain and muscle accumulate somatic mtDNA mutations with age. Because individual mtDNA mutations are present at very low levels, few details are known about the spectrum of mutations associated with aging.

Advances in sequencing technology now permit the examination of mtDNA mutations at high resolution. We have examined the spectrum of mtDNA mutations present in putamen, a brain region prone to the accumulation of somatic mtDNA mutations. We were able to quantify the accumulation of clonal and non-clonal deletions in the mtDNA coding region which are known to have a strong association with aging. Partial deletions and novel duplications of the mtDNA control region were also identified, and appear to be more prevalent than previously recognized, but levels showed weaker associations with age than coding region deletions. Single nucleotide variants accumulate fastest in the control region, with a skew towards the accumulation of pathogenic mutations in the coding region.

Understanding how the mitochondrial genome alters with age provides a benchmark for studies of somatic mtDNA mutations and dissection of the role they play in normal aging and degenerative diseases.

Tuesday, March 18, 2014

One aspect of nerve regeneration is the reconstruction of lost or severed axons, the long connecting threads that link neurons in the nervous system. Some of this damage can regenerate naturally, but as for most of the critical functions of our biology this regenerative ability declines with age. Here researchers note a possible cause, the first step towards some form of treatment or reversal of age-related loss of function:

Injuries to peripheral nerves can cause paralysis and sensory disturbances, but such functional impairments are often short lived because of efficient regeneration of damaged axons. The time required for functional recovery, however, increases with advancing age. Incomplete or delayed recovery after peripheral nerve damage is a major health concern in the aging population because it can severely restrict a person's mobility and independence.

A variety of possible causes have been suggested to explain why nervous systems in aged individuals recover more slowly from nerve damage. Potential causes include age-related declines in the regenerative potential of peripheral axons and decreases in the supply or responsivity to trophic and/or trophic factors. However, there have been few direct analyses of age-related axon regeneration. Our aim here was to observe axons directly in young and old mice as they regenerate and ultimately reoccupy denervated neuromuscular synaptic sites to learn what changes in this process are age related.

We find that damaged nerves in aged animals clear debris more slowly than nerves in young animals and that the greater number of obstructions regenerating axons encounter in the endoneurial tubes of old animals give rise to slower regeneration. Surprisingly, however, axons from aged animals regenerate quickly when not confronted by debris and reoccupy neuromuscular junction sites efficiently. These results imply that facilitating clearance of axon debris might be a good target for the treatment of nerve injury in the aged.

Wednesday, March 19, 2014

Here is news of a recent demonstration of the use of stem cells in nerve regeneration:

Stem cells derived from human muscle tissue were able to repair nerve damage and restore function in an animal model of sciatic nerve injury. The researchers [found] that, with prompting from specific nerve-growth factors, the stem cells could differentiate into neurons and glial support cells, including Schwann cells that form the myelin sheath around the axons of neurons to improve conduction of nerve impulses.

In mouse studies, the researchers injected human muscle-derived stem/progenitor cells into a quarter-inch defect they surgically created in the right sciatic nerve, which controls right leg movement. Six weeks later, the nerve had fully regenerated in stem-cell treated mice, while the untreated group had limited nerve regrowth and functionality. Twelve weeks later, treated mice were able to keep their treated and untreated legs balanced at the same level while being held vertically by their tails. When the treated mice ran through a special maze, analyses of their paw prints showed eventual restoration of gait. Treated and untreated mice experienced muscle atrophy, or loss, after nerve injury, but only the stem cell-treated animals had regained normal muscle mass by 72 weeks post-surgery.

Wednesday, March 19, 2014

We humans live for much longer than the other large primates, and the grandmother hypothesis suggests that this longevity evolved because of our greater capacity for culture, cooperation, and communication. Once we became intelligent enough for older and less physically capable individuals to nonetheless materially assist in the survival of their descendants, longer lives were selected for.

As is the case for other theories in the evolution of aging, simulation is used to investigate the grandmother hypothesis and bolster arguments on interpretation and plausibility. Here, the researchers suggest that enhanced longevity in our ancestors in comparison to their primate peers may have predated our species:

We present a mathematical model based on the Grandmother Hypothesis to simulate how human post-menopausal longevity could have evolved as ancestral grandmothers began to assist the reproductive success of younger females by provisioning grandchildren. Grandmothers' help would allow mothers to give birth to subsequent offspring sooner without risking the survival of existing offspring. Our model is an agent-based model (ABM), in which the population evolves according to probabilistic rules governing interactions among individuals. The model is formulated according to the Gillespie algorithm of determining the times to next events. Grandmother effects drive the population from an equilibrium representing a great-ape-like average adult lifespan in the lower twenties to a new equilibrium with a human-like average adult lifespan in the lower forties.

The stochasticity of the ABM allows the possible coexistence of two locally-stable equilibria, corresponding to great-ape-like and human-like lifespans. Populations with grandmothering that escape the ancestral condition then shift to human-like lifespan, but the transition takes longer than previous models. Our simulations are consistent with the possibility that distinctive longevity is a feature of genus Homo that long antedated the appearance of our species.

Thursday, March 20, 2014

The pension and annuity industries and even some of the individual companies involved are truly massive. Vast sums are at play over the course of decades, and these industries will be greatly impacted by advances in means of extending healthy human longevity. Those involved are well aware of this: their challenge is not the fact that human lives will grow longer, but rather that there is great uncertainty over the upper limits to that growth. We are no longer in an era in which it is safe to extend the slow upward trend in adult life expectancy: work such as that of the SENS Research Foundation or any of dozens of other scientific groups could contribute to a sudden leap in healthy life span by producing the means of at least partial rejuvenation.

This is a challenge for the annuity and pension giants because in providing their services they have effectively taken on bets against a large increase in life span within our lifetimes. They will be ruined, or more likely they will taken on a form of insurance themselves and their counterparties in the broader financial industry will implode. Equally these entities are so large and have so much leverage that they will be able to have politicians bail them out, transferring the cost of being wrong to the public purse. It will be something like the fallout from the US real estate bubble, and another symptom of much that is wrong with the existence of highly centralized, powerful states and governance.

Various entities around the world are taking half-steps in the direction of reducing their financial exposure to increasing longevity - which might be an indication of what people really think about the prospects for greater longevity arising from medical science, if they have enough money at stake to carefully investigate the issue. Cynically, this might be thought of as a shifting of risk onto larger financial parties willing to take it on because they know they can engineer a state bailout at the end of the day. This is an example of the type, not particularly important in and of itself, but representative of the flow of money and responsibilities presently underway in response to changing expectations on the future of human longevity:

A Canadian company has signed an agreement to outsource its pension plan risk by buying about $500-million of annuities, spotlighting the growing interest in such purchases from companies eager to reduce the volatility of their retirement plans. The agreement, which is the largest group annuity deal of its kind in Canada, echoes a pattern that is already well established in the United States and Britain, as companies seek to "de-risk" defined-benefit pension plans.

The deals are popular because they remove companies' long-term pension risks and reduce future income volatility. "They are talked about such a lot now that it seems inevitable to me that we're going to see more of these set up."

Under a "pension buy-in," an insurer essentially takes over the risk of funding a firm's pension payments by selling the firm annuities with guaranteed payout rates to match the size of the pension obligation. The company still has ultimate responsibility for the pension plan and remains the pension plan's sponsor, and the deal does not affect the level of benefits owed or paid to retirees.

For years, U.S. and British companies have structured deals to shift the risk of their pension obligations to a third-party insurer. General Motors Co., for example, did a $26-billion (U.S.) annuity deal in 2012 to shift the obligation for its pension plan off its books, while Verizon Communications Inc. completed a $7-billion annuity deal for its pension plan in 2012.

Thursday, March 20, 2014

Differences in resting metabolic rate (RMR) between species of mammal correlate well with differences in life span. It has also been found that in our species RMR declines with advancing age, and a higher RMR is predictive of a greater risk of death. This study confirms these associations:

To assess the associations among age, health status, and resting metabolic rate (RMR) in a large population of older adults from the Baltimore Longitudinal Study of Aging (BLSA): 420 persons aged 40 to 96 (mean 68.2 ± 11.0) who underwent a comprehensive physical examination, cognitive assessment, RMR testing, body composition assessment, and physical function testing during a 3-day clinic visit.

Participants were assigned to Insight into the Determination of Exceptional Aging and Longevity (IDEAL) or non-IDEAL categories based on health status. IDEAL participants were defined according to the absence of physical and cognitive impairments, chronic conditions and comorbidities, and blood profile abnormalities. A three-stage linear regression model was used to assess the relationship between RMR and age, using IDEAL classification as a predictor and adjusting for sex and body composition.

Resting metabolic rate averaged 1,512.4 ± 442.9 kcal/d and was lower with older age. After adjusting for age, sex, and body composition, RMR was 109.6 kcal/d lower in IDEAL than non-IDEAL participants. Individuals who are fully functional and free of major medical conditions have lower RMR than those with disease and functional impairments. These findings suggest that health status plays a role in energy use and regulation independent of age and body composition and that elevated RMR may be a global biomarker of poor health in older persons.

Friday, March 21, 2014

Bone density declines with aging, a condition known as osteopenia, and which leads to the serious frailties of osteoporosis. One of the possible reasons for this is a growing deficiency in osteoblasts, the cells that lay down bone structure, or perhaps a widening mismatch between the behavior of osteoblasts and osteoclasts, the cells responsible for breaking down bone structure when needed. Here, researchers look into some of the details of osteoblast deficiency, and find it is complex, with differing mechanisms between the genders:

Bones adjust their mass and architecture to be sufficiently robust to withstand functional loading by adapting to their strain environment. This mechanism appears less effective with age resulting in low bone mass. In male and female young adult (17 week) and old (19 month) mice we investigated the effect of age in vivo on bones' adaptive response to loading and in vitro in primary cultures of osteoblast-like cells derived from bone cortices.

Right tibiae were axially loaded on alternate days for 2 weeks. Left tibiae were non-loaded controls. In a separate group, the number of sclerostin positive osteocytes and the number of periosteal osteoblasts were analyzed 24 hours after a single loading episode. In young male and female mice loading increased trabecular thickness and the number of trabecular connections. Increase in the number of trabecular connections was impaired with age but trabecular thickness was not. In old mice the loading-related increase in periosteal apposition of the cortex was less than in young ones. Age was associated with a lesser loading-related increase in osteoblast number on the periosteal surface but had no effect on loading-related reduction in the number of sclerostin positive osteocytes. In vitro, strain-related proliferation of osteoblast-like cells was lower in cells from old than young mice. Cells from aged female mice demonstrated normal entry into the cell cycle but subsequently arrested in G2-phase, reducing strain-related increases in cell number.

Thus in both male and female mice loading-related adaptive responses are impaired with age. This impairment is different in females and males. The deficit appears to occur in osteoblasts' proliferative responses to strain rather than earlier strain-related responses in the osteocytes.

Friday, March 21, 2014

A popular science piece on a new association in the biochemistry of Alzheimer's disease:

It is one of the big scientific mysteries of Alzheimer's disease: Why do some people whose brains accumulate the plaques and tangles so strongly associated with Alzheimer's not develop the disease? The memory and thinking problems of Alzheimer's disease and other dementias, which affect an estimated seven million Americans, may be related to a failure in the brain's stress response system, the new research suggests. If this system is working well, it can protect the brain from abnormal Alzheimer's proteins; if it gets derailed, critical areas of the brain start degenerating.

The research focuses on a protein previously thought to act mostly in the brains of developing fetuses. The scientists found that the protein also appears to protect neurons in healthy older people from aging-related stresses. But in people with Alzheimer's and other dementias, the protein is sharply depleted in key brain regions.

"Why should a fetal gene be coming on in an aging brain?" [Researchers] hypothesized that it was because in aging, as in birth, brains encounter great stress, threatening neurons that cannot regenerate if harmed. [Researchers] discovered that REST appears to switch off genes that promote cell death, protecting neurons from normal aging processes like energy decrease, inflammation and oxidative stress.

In people with Alzheimer's, mild cognitive impairment, frontotemporal dementia and Lewy body dementia, the brain areas affected by these diseases contained much less REST than healthy brains.This was true only in people who actually had memory and thinking problems. People who remained cognitively healthy, but whose brains had the same accumulation of amyloid plaques and tau tangles as people with Alzheimer's, had three times more REST than those suffering Alzheimer's symptoms. About a third of people who have such plaques will not develop Alzheimer's symptoms, studies show.


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