Fight Aging! Newsletter, February 17th 2014

February 17th 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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  • The Decade to Come in Which Treatments for Aging Exist, But Are Largely Illegal
  • Ray Kurzweil Expounds on the SENS Rejuvenation Biotechnology of Allotopic Expression
  • Visual Measurement of Mitochondrial Free Radicals Predicts Longevity in Nematodes
  • Silencing p16 to Reverse Senescence in Old Muscle Stem Cells
  • Greater Personal Wealth Makes Being Old Seem More Tolerable
  • Latest Headlines from Fight Aging!
    • Metabolomics Data From Centenarians
    • Mitochondrially Targeted Antioxidant Delays Age-Related Structural Changes in Mitochondria
    • A Specific Example of Harm Caused By Senescent Cells
    • The Persistent Mistaken Belief that Rejuvenation Will Be Only for the Wealthy
    • Suggesting that Mitochondrial DNA Damage Doesn't Result From Oxidative Stress
    • Age-Related Changes Observed in Neuromuscular Synapses
    • Searching For Correlations Between Longevity and Natural Variations in DNA Repair Machinery
    • A Possible Target to Spur Remyelination of Nerves
    • More Investigations of the Effects of CMV in the Old
    • Commentary on the Evolution of Aging


We are fairly close to the existence of the first meaningful treatments for aging, therapies that align with the SENS approach of repairing the fundamental forms of damage in tissues and cells that cause aging. From the speculative list I put forward a year or two ago, we could look at the first item, removal of senescent cells. Nothing much would have to change about research funding or current directions for a therapy based on targeted removal of senescent cells to be entering human clinical trials in the mid 2020s. That therapy will be aimed at one specific age-related condition, not aging itself, because that is how medical regulation works: it is illegal to try to treat aging, there is no path to gain approval to treat aging, and so any promising technology is sidelined into use as a late stage treatment for people who are especially sick. Which is to say they are damaged enough by aging, and manifest one of its outcomes to a large enough degree that we give it a name and call it a disease or a condition. Whereupon it becomes legal to try to treat just that one facet of aging - or at least to try to convince regulators you should be allowed to treat it. Everyone who is damaged by aging to a lesser degree is called healthy and denied access to therapies.

This world of ours is packed with iniquity, unfairness, and stupidity, but the organization of medical regulation is of particular note. So, I'd predict that by 2025 there will probably exist a treatment for removal of senescent cells that would be of benefit to everyone much over the age of 30. However, it will be highly restricted - essentially illegal for use, illegal to provide to people, and illegal to aid people in using it. That is the state of the law for any advanced medical technology not approved by the FDA.

Now consider the way in which research and the clinical application of stem cell treatments has progressed over the past decade. Medical tourism emerged even in the comparatively early days, as soon as the trend towards greater reliability and lower cost for stem cell transplants started in earnest. Many clinics of varying levels of sophistication outside the US have for years offered procedures that until comparatively recently remained forbidden and illegal within the US. I'd judge that it was largely the existence of that growing market that pressured the FDA into allowing the use of these technologies - long years after they became available elsewhere. FDA leaders operate under incentives that don't align with yours: they are driven by how much public disfavor they receive, which means approving as few new technologies as possible, as they are blamed for any consequences, until such time as being a roadblock earns more disfavor than letting things through. Quality of medicine and any other declared aims of the organization are somewhat lower in the decision tree. You can look at the rapidly increasing cost of regulatory compliance, capricious demands placed on developers, and the falling number of approvals for technologies, drugs, and so forth as evidence for this viewpoint.

Given how things went for stem cells, it will be interesting to see what will happen in the case of legitimate treatments for aging that we would expect to lengthen human life in every recipient, but which are only available for the most damaged and closest to death. By 2025 we will know how much senescent cell removal lengthens life in rodents, but it will be speculation as to what exactly the benefit is for people in the long term: short term biomarker changes will be measured and found to be supportive of the idea that the treatment is improving health and turning back metabolic metrics of biological age, but that still doesn't say much about what the outcome is at the end of the day. Improvement in health is expected, but I think that the current view of SENS is that only complete implementation should be expected to radically lengthen life.

Still, imagine the availability of a "stem cell treatment for everyone" that would benefit you just as much as the stem cell transplants of five to ten years ago were of benefit to victims of heart disease. This will happen, and comparatively soon. It might be worth considering how to accelerate the wave, or use it to gain greater funding and interest for the other lines of SENS research aimed at human rejuvenation.


Way back when, Ray Kurzweil put in a good word and modest donation to assist the early growth of the Methuselah Foundation and SENS rejuvenation research. He was one of the first to do so. Since then, however, I really don't recall seeing mention of SENS or specific branches of SENS-like biological repair research from Kurzweil in public media appearances, through you'll certainly find that sort of material in his books. He generally focuses on applied neuroscience, strong AI, mind-machine interfaces, and that sort of thing.

So this article caught my eye, and those of you who are waiting to see what Google's Calico venture will do can add this to your collection of hopeful prognosticator's tea leaves. Here Kurzweil gives a layperson's overview of the SENS approach of allotopic expression of mitochondrial DNA, a way to make the age-related accumulation of damage to mitochondrial DNA irrelevant and thus remove it as as a contributing cause of degenerative aging:

Google's Kurzweil says the machines will think for themselves by 2040, and oh - we'll be immortal

Kurzweil is also involved in one of Google's other side projects, Calico, which is about as far from the company's core search-revenue business model as possible. It's doing medical and genetic research with the goal of ending aging. It's something Kurzweil thinks is possible to do through genetic re-engineering.

The example he gave here is mitochondria, a component of every living cell that metabolizes energy and is critical to life. Mitochondria started out as a kind of bacteria that were captured and consumed by living cells many, many eons ago, Kurzweil said. Consequently, they have their own genome separate from the rest of the body, stored in separate DNA from the cell's nucleus.

Mitochondrial DNA is more prone to errors as the cell replicates itself, which can lead to a host of health problems. Kurzweil said that nature actually addressed this by moving much of the mitochondrial genetic code into the nucleus where it could be stored in less error-prone DNA. But because of the way natural selection works, this process stopped before it moved some bits of the code which only come into use later in life, after a person would have normally reproduced. Kurzweil thinks humans can finish this process and solve some of the deleterious effects of aging.

One would hope that there are also other advocates for aspects of SENS inside Google these days, though so far the known hires to lead Calico are people with far more sympathy for the doomed mainstream approach of drug development after the calorie restriction mimetic model, aiming only to slightly slow aging, and with no hope of significant progress towards longer lives on the timescale that full funding of SENS could provide.


Researchers have engineered a clever system to visually determine levels of free radical activity in the mitochondria of nematode worms, something that can be automated to a fairly high degree, which in turn enables the collection of much more data, leading hopefully to more rigorous conclusions. The same approach could be employed in other species, such as mice, though it would take much longer and require more manual effort - such as regular tissue sampling in a population of mice - to run the same experiments to correlate levels of mitochondrial free radical production to life span.

Mitochondria are important in the aging process because they are central to many vital cellular processes, but suffer damage to their DNA - the blueprints for their component proteins - as the result of free radicals emitted in their normal operation. Or perhaps it isn't due to free radical damage but more a matter of mistakes occurring during DNA replication: mitochondrial DNA doesn't benefit from the same level of quality control and repair machinery as does the DNA in the cell nucleus. Regardless of whether free radical levels are causing harm in this way, they are also important to the operation of metabolism through other channels. Different longevity-inducing mutations have been noted to either raise and lower the normal levels of free radical generation in various species. So on the one hand it is argued that hormetic effects cause a boost in repair mechanisms throughout the cell, producing a net benefit despite more free radicals running around, while on the other hand its also argued that reducing levels of free radicals leads to less damage in the first place and thus much the same net benefit.

Equally, any or all of these longevity mutations could be extending life through other mechanisms that have less to do with free radicals: there is a lot of room yet for theorizing even though the mainstream consensus heavily favors oxidative damage as an important mechanism. Understanding the operations of the cell is a complex business for individual cells, never mind a whole body full of them.

The importance of this present research quoted below is as a reference system, one that can be ported to other species to generate better hard data on what exactly is going on with regard to free radical levels across a life span. That will make it much easier in the years ahead to pin down cause and effect in a variety of mechanisms related to mitochondria - I can immediately think of half a dozen things I'd like to see tested in conjunction with a form of this technology ported to mice.

Lifespan predicted from flashes in worm cells

[Researchers] added proteins to nematode worms that fluoresce when they detect damaging free radical molecules in their mitochondria. Mitochondria generate a cell's energy. It's long been thought that an accumulation of free radicals, produced when cells metabolise, drives the ageing process by damaging DNA and proteins. Mitochondria are particularly at risk because they produce free radicals in large quantities but lack the DNA repair mechanisms found in other parts of the cell.

[The] team found that the number of "mitoflashes", caused by the presence of free radicals, emitted when a nematode was three days old could predict its lifespan. Worms typically live for 21 days and are at their peak of reproductive fitness at 3 days old. Those with low mitoflash activity at that time lived longer, while those with high mitoflash activity died before day 21.

Worms carrying a genetic mutation known to extend life to 39 days exhibited fewer mitoflash bursts than genetically healthy worms, and free radical production peaked later in their lifespan. Conversely, worms with a life-shortening mutation exhibited much higher than average mitoflash frequency which peaked earlier.

The same pattern was seen when the team exposed the worms to short periods of starvation and heat shock, environmental stresses that counter-intuitively increase lifespan, and to a toxic herbicide known to shorten lifespan.

Mitoflash frequency in early adulthood predicts lifespan in Caenorhabditis elegans

It has been theorized for decades that mitochondria act as the biological clock of ageing, but the evidence is incomplete. Here we show a strong coupling between mitochondrial function and ageing by in vivo visualization of the mitochondrial flash (mitoflash), a frequency-coded optical readout reflecting free-radical production and energy metabolism at the single-mitochondrion level.

Mitoflash activity in Caenorhabditis elegans pharyngeal muscles peaked on adult day 3 during active reproduction and on day 9 when animals started to die off. A plethora of genetic mutations and environmental factors inversely modified the lifespan and the day-3 mitoflash frequency. Even within an isogenic population, the day-3 mitoflash frequency was negatively correlated with the lifespan of individual animals.

Furthermore, enhanced activity of the glyoxylate cycle contributed to the decreased day-3 mitoflash frequency and the longevity of daf-2 mutant animals. These results demonstrate that the day-3 mitoflash frequency is a powerful predictor of C. elegans lifespan across genetic, environmental and stochastic factors. They also support the notion that the rate of ageing, although adjustable in later life, has been set to a considerable degree before reproduction ceases.


Ever more cells in our tissues become senescent with age, entering a program of behavior that appears to be - at least partially - an adaptation to suppress cancer. A senescent cell leaves the cell cycle, stops dividing, and starts to emit signaling molecules that harm surrounding tissues and encourage other cells to become senescent. Some senescent cells destroy themselves or are killed by the immune system, but their numbers still grow greatly in later life. This degrades health and contributes to the pathology of age-related diseases.

Senescence is distinct from quiescence, the other state in which a cell stops dividing: quiescent cells offer no harm and are generally well-behaved. Many populations of stem cells, for example, spend most of their time in a quiescent state, awaiting the call to action or periodic revival to maintain tissues by generating replacement cells. In recent work, researchers suggest that senescence is a reaction to simultaneous signals telling a cell to replicate and not replicate: the need to maintain tissues (go forth and multiply) combined with high levels of cellular damage (stay put because it is too risky to act), for example.

An intriguing interpretation of cell senescence postulates that this unique phenotype emerges when a cell integrates two types of signals: one that reads for growth and one that imposes a block in the replicative cycle. For example, DNA damaging agents do not induce senescence in quiescent cells; however, they do so if the presence of persistent DNA damage and cell cycle arrest is coupled with growth promoting stimuli. Under these conditions, cells switch on the senescence program and express markers related to both cell cycle block and growth stimulation.

Building on this vision, below you'll find another look at the triggering of senescence in aged stem cells - muscle stem cells this time, important to the progression of sarcopenia, the loss of muscle mass and strength with aging. One of the possible approaches to senescent cells, and probably the easiest, is to remove them using some form of targeted cell destruction technology of the sort under development in the cancer research community. Another approach is to try to reverse senescence: if it is largely a reaction to damage, it might be the case that repair of cellular damage in the SENS model of rejuvenation biotechnology will result in reduced levels of cellular senescence. Alternatively scientists could aim to brute force the process by overriding signaling processes without addressing the underlying causes of signaling changes, which is the approach taken in most modern medical research, and that offered here.

Geriatric muscle stem cells switch reversible quiescence into senescence

Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline with ageing. Here we report that geriatric satellite cells are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and that this irreversibly affects their intrinsic regenerative and self-renewal capacities.

In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16INK4a (also called Cdkn2a). On injury, these cells fail to activate and expand, undergoing accelerated entry into a full senescence state (geroconversion), even in a youthful environment.

p16INK4a silencing in geriatric satellite cells restores quiescence and muscle regenerative functions. Our results demonstrate that maintenance of quiescence in adult life depends on the active repression of senescence pathways. As p16INK4a is dysregulated in human geriatric satellite cells, these findings provide the basis for stem-cell rejuvenation in sarcopenic muscles.

It is promising to see yet another study demonstrating that old stem cells retain the potential to do their jobs. The p16 gene is clearly going to be an increasingly important research topic in the years ahead based on its close connection with cellular senescence.


Until you get to the point of retirement or incapacity, being older tends to mean being wealthier and more influential in your community: you are earning, saving, and interacting with people, and that adds up over the years. In the first stages of aging, when all you have suffered are comparatively minor pains, dysfunctions, and losses, being financially secure and well-connected in comparison to earlier years is a significant compensation. If you ask people in their 40s whether they would trade their present security, influence, and network for the flush (and lack of resources) of youth, then you might see some careful weighing of options.

Life is a progression from a place of time, health, and no resources to a place of resources but neither health nor time, and these line items are valued accordingly at each stopping point along the way. So we see people spending vast sums on medical technology in the last stages of life, not just because it is enormously costly to try to compensate for or patch over the end of aging with the techniques available today, but more importantly because these people consider such an expense worth it. What were unthinkable sums for the poorer, younger version of an individual are spent on obtaining a little more time or small gains in freedom from pain and disability. The future of rejuvenation biotechnology will liberate us from these cruel calculations, and that goal is precisely why it is important.

How people perceive their own well-being depends in part on wealth: up to a level of diminishing returns the more you have the better you feel about life. So the natural progression of increasing wealth with age is probably one (perhaps minor) contributing cause of a level of disinterest in work on lengthening healthy life and creating rejuvenation. People are moved to action by dissatisfaction and discomfort to a greater degree than by ideals, I think. If you are more or less comfortable where you are, and none your neighbors are one-upping you with those newfangled rejuvenation therapies, then why make the effort?

Researchers here are putting some numbers to the relationship between wealth, health, and how people feel about being old. Their results suggest much as above, that wealth - and all that comes with it - is compensatory, but only up to a point. Which is something to think about while you are in your 30s and 40s and on top of the world.

Frailty, financial resources and subjective well-being in later life

Though frailty status has recently been linked to poorer quality of life, the impact of income on this relationship has not previously been investigated. Data from a population-based panel study, the English Longitudinal Study of Aging, on 3225 participants aged 65-79 years were analyzed cross-sectionally.

A Frailty Index (FI) was determined for each participant as a proportion of accumulated deficits and participants were categorized into four groups on the basis of their FI score: very fit (0.00-0.10), well (0.11-0.14), vulnerable (0.15-0.24), and frail (≥0.25). Subjective well-being was assessed using the CASP-19 instrument, and levels of financial resources quantified using a range of questions about assets and income from a range of sources.

Linear regression models were used to assess the relationship between frailty and well-being. There was a significant negative correlation between frailty and well-being; the correlation coefficient between FI and CASP-19 scores was -0.58. The relationship was robust to adjustment for sex, age, and relevant health behaviors (smoking and physical activity) and persisted when participants with depressive symptoms were excluded from analysis.

Those with greater financial resources reported better subjective well-being with evidence of a "dose-response" effect. The poorest participants in each frailty category had similar well-being to the most well-off with worse frailty status. Hence, while the association between frailty and poorer subjective well-being is not significantly impacted by higher levels of wealth and income, financial resources may provide a partial buffer against the detrimental psychological effects of frailty.


Monday, February 10, 2014

Researchers continue their investigations into the biochemical differences between extremely long-lived individuals and the rest of us:

In the present study we have expanded our previous investigation on metabolic signatures of longevity by integrating a system biology approach in serum on a representative North Italian cohort of aged subjects, compromising elderly and centenarians. Data on centenarians in particular are of interest, as they are considered the best example of successful aging having reached the very extremes of the human lifespan. It is worth noting that the metabolic signatures described in this paper reflect mostly female individuals, as male centenarians are much more rare than female ones, and in particular in the north of Italy the male/female ratio is about 1:7.

By combining NMR metabonomics and shot-gun lipidomics in serum we analyzed metabolome and lipidome composition of a group of centenarians with respect to elderly individuals. Specifically, NMR metabonomics profiling of serum revealed that centenarians are characterized by a metabolic phenotype distinct from that of elderly subjects, in particular regarding amino acids and lipid species. Shot- gun lipidomics approach displays unique changes in lipids biosynthesis in centenarians, with 41 differently abundant lipid species with respect to elderly subjects. These findings reveal phospho/sphingolipids as putative markers and biological modulators of healthy aging, in humans.

The represented changes reflect that longevity is marked by better antioxidant capacity and a well-developed membrane lipid remodelling process able to maintain cell integrity. Moreover, in the light of very recent data indicating glycerophosphocholine as a circulating marker related to cell senescence, our data are suggestive of the fact that centenarians are characterised by lower levels of cell senescence with respect to old subjects. As a whole, these data support the hypothesis that from a metabolic point of view centenarians are younger than their chronological age.

Monday, February 10, 2014

Mitochondrial damage is a contributing cause of aging. It happens as a natural side-effect of mitochondrial operation because mitochondria generate a flow of damaging reactive oxygen species (ROS) in the course of creating chemical energy stores to power the cell. The most likely target for these ROS? The mitochondria themselves.

Mitochondrial repair technologies and the SENS approach of creating backup mitochondrial genes in the cell nucleus are promising approaches to removing this contribution to aging. A less promising approach is to target engineered antioxidant compounds to the mitochondria to augment natural antioxidants and soak up some of those ROS before they cause harm. This is less promising because it can only slow down the process.

Here is the latest from one of the various programs of development for mitochondrially targeted antioxidants:

Sarcopenia, the gradual loss of muscle mass and function, is a common feature of human aging. The molecular mechanisms leading to sarcopenia are not completely identified, but the retardation [of] oxidative damage entailed with an age-linked mitochondrial dysfunction occurring in the muscle cells looks as promising approach to treat this disease.

Our study of skeletal muscles [of] Wistar rats have revealed age-related changes in the amount of mitochondria, forms of mitochondrial profiles and ultrastructure. The treatment of animals with a mitochondria-targeted antioxidant SkQ1 retarded development of age-related destructive pathological changes in mitochondria of both Wistar and OXYS rats. Again, this is true for the amount of mitochondria, the development of mitochondrial reticulum and ultrastructure of the mitochondrial cristae.

Accumulating evidence supports the existence of a close relationship between declining anabolic hormones, such as growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels and age-related changes in body composition and function. Therefore, the age-dependent decline of GH and IGF-1 serum levels might promote the loss of muscle mass and strength. We recently measured the levels of these hormones in the SkQ1-treated animals. It was found that an SkQ1 treatment between the ages of 19 and 23 months increased the blood levels of GH and IGF-I in the Wistar and the OXYS rats above those found in the 19 month-old animals. These results suggest that the effect of the SkQ1 against sarcopenia may be partially mediated by an activation of somatotropic (GH/IGF-1) signaling which is reduced in OXYS rats since a young age.

Tuesday, February 11, 2014

Here's a detailed look at one narrow form of dysfunction caused by the accumulation of senescent cells in tissue. Senescent cells gather with age in all tissues, and similar processes are thought to take place throughout the body - which is why targeted removal of senescent cells is an important part of any future toolkit for rejuvenation:

Renal aging is associated with an increased susceptibility to acute stress and tubular cell injury. While the young kidney has a remarkable capacity to recover from acute injury, the aging kidney loses this repair reserve and instead develops an increasing tendency for tubular atrophy and interstitial fibrosis. Our previous data suggest that a loss in tubular epithelial proliferative reserve contributes importantly to inappropriate repair in the aged kidney.

Under baseline conditions the renal tubular epithelium has a low rate of cellular turnover when compared to other tissues. In mouse kidney less than 1% of proximal tubular cells express proliferation markers under normal conditions. In response to acute damage, however, the renal epithelium can initiate a burst of proliferation which serves to repopulate and restore injured tubules. This injury-response may lead to full functional recovery even after extensive tubule denudation.

We have previously shown that the proliferative potential of tubular cells declines with chronological age. In previous studies we linked the inability to increase cell cycling to somatic cellular senescence (SCS) by demonstrating that genetic induction of telomere shortening, as a model of telomere dependent SCS in mice, was associated with a decline in the tubular proliferative capacity. Ablation of the pro-senescent p16INK4A, on the other hand, resulted in improved regeneration and better proliferation following acute ischemic renal injury.

Tuesday, February 11, 2014

There is something about using medicine to treat aging that inspires otherwise sensible people to hold all sorts of obviously mistaken beliefs, utterly disconnected from the way in which the world actually works. For example that only the wealthy will ever have access to rejuvenation therapies developed in the next few decades. Yet these treatments will be simply another new form of medicine, no different in essence from the new forms of medicine introduced with great regularity over the past century. Each new advance was briefly expensive and unreliable, with only limited availability, and then within a decade or two became widely available, more reliable, and much less expensive. This is how progress works, driven by the economics of the marketplace.

Our age is characterized by the fact that there is very little in the way of technology that can only be afforded by the very wealthy - and next to none of that is in the field of medical science. Look at those people claiming that future medicines will be available only to the wealthy, and place them in the 1940s; have them argue that soon to arrive heart surgery and other treatments for heart disease will only be available to the very wealthy elite, who will restrict access for the masses. It is the same argument, mistaken for the same reasons.

There are many obvious differences between the attempt to use science to cheat death that was mounted nearly a century ago in Russia and the one that is attracting support in Silicon Valley today. Human knowledge, and with it technology, has moved on greatly. Advances in neuroscience, information technology and artificial intelligence have shifted the focus from cryonics to the more radical prospect of freeing the human mind from its fleshly envelope. At the same time, genetic engineering and nanotechnology have been hailed as opening up the possibility of halting or reversing physical aging. According to some of the boldest promoters of technological immortality, there is a real prospect that these new sciences will make it possible for humans to live forever.

While the mystic who inspired Russian techno-immortalists dreamt of resurrecting everyone, his disciples were more selective. It was exceptional human beings such as Lenin they were most interested in reviving. Any remedy for mortality would also be highly selective today. Russian prophets of a future without death imagined the advance of humanity being planned as part of a communist planned economy, while those in Silicon Valley are ardent enthusiasts for capitalism. But whatever the economic system, life extension is a costly business whose benefits will in practice be distributed very unequally.

The prospect of a society in which existing inequalities are accentuated, with the richest living several times longer than the mass of the population, is not exactly enticing. Nor would such a brutally divided society be likely to be stable.

Some people like to twist the narrative to support their own strange views. Longevity-enhancing treatments will not be expensive once they have passed their initial period of unreliable, limited early clinical development. They are not like surgeries, in which a team of highly skilled and comparatively rare individuals must be hands-on for the better part of a day. They are more like infusions or injections, in which a much more common and less skilled medical professional performs a simple operation in a matter of minutes to introduce the treatment into the body. So I foresee thousands, not hundreds of thousands of dollars as the ballpark price per treatment.

Wednesday, February 12, 2014

Mitochondria are the power plants of the cell: they produce chemical energy stores and participate in an important way in numerous other vital cellular processes. Mitochondria contain their own DNA, left over from their past existence as symbiotic bacteria, and damage to this mitochondrial DNA is a contributing cause of aging. The conventional view is that this damage arises when the reactive oxygen species produced by mitochondria in the course of their normal operation react with the nearby DNA. This is supported by a wide range of evidence, such as the fact that antioxidants targeted to mitochondria extend life.

These researchers offer evidence in support of another view - that oxidative stress doesn't matter, and the damage that contributes to aging occurs during mitochondrial replication. This view leaves numerous open questions, such as what is happening to extend life via targeted antioxidants:

Mitochondria are the evolutionary remnants of bacteria that were acquired by the cells of our ancestors more than a billion years ago and now produce virtually all of the cellular energy. Due to their bacterial ancestry, mitochondria have their own genomes, which encode some of the machinery responsible for producing energy. These genes occasionally acquire mutations - irreversible alterations that can adversely affect the energy production machinery. The accumulation of mitochondrial DNA (mtDNA) mutations is thought to cause aging and common age-related diseases, but we know little about the factors that influence the frequency of these mutations.

Our study tested whether fruit flies would serve as a good animal model to study this problem. We found that flies accumulate mtDNA mutations in a pattern similar to that of humans. We then used flies to test the long-standing theory that toxic free radicals, chemical byproducts of energy production, cause mtDNA mutations to accumulate. Our data do not support this hypothesis, and instead suggest that rare errors associated with duplicating mitochondrial genomes are primarily responsible for mtDNA mutations. In sum we demonstrate that Drosophila serves as a tractable genetic model to investigate the mechanisms that influence the frequency of somatic mtDNA mutations.

Wednesday, February 12, 2014

Researchers here make an observation of this change, but the proximate causes remain to be established. The root causes are presumably the same as for the rest of aging - the accumulation of cellular and molecular damage, and evolved reactions to that damage.

[Researchers] report the first evidence that "set points" in the nervous system are not inalterably determined during development but instead can be reset with age. They observed a change in set point that resulted in significantly diminished motor function in aging fruit flies. "The body has a set point for temperature (98.6 degrees), a set point for salt level in the blood, and other homeostatic (steady-state) set points that are important for maintaining stable functions throughout life. Evidence also points to the existence of set points in the nervous system, but it has never been observed that they change, until now."

[The team] recorded changes in the neuromuscular junction synapses of aging fruit flies. These synapses are spaces where neurons exchange electrical signals to enable motor functions such as walking and smiling. "We observed a change in the synapse, indicating that the homeostatic mechanism had adjusted to maintain a new set point in the older animal." The change was nearly 200 percent, and the researchers predicted that it would leave muscles more vulnerable to exhaustion.

Aside from impairing movement in aging animals, a new functional set point in neuromuscular junctions could put the synapse at risk for developing neurodegeneration - the hallmark of disorders such as Alzheimer's and Parkinson's diseases. It appears that a similar change could lead to effects on learning and memory in old age. An understanding of this phenomenon would be invaluable and could lead to development of novel therapies for those issues, as well.

Thursday, February 13, 2014

Genetic errors leading to major DNA repair dysfunction cause a variety of conditions that look a lot like accelerated aging, at least in some aspects of their progression. Here researchers examine small variations in genes associated with DNA repair in a human population, but - as is usually the case in studies of human genetic variation - fail to find a robust correlation with longevity, or one that holds up across different data sets:

DNA-damage response and repair are crucial to maintain genetic stability, and are consequently considered central to aging and longevity. Here, we investigate whether this pathway overall associates to longevity, and whether specific sub-processes are more strongly associated with longevity than others. Data were applied on 592 SNPs from 77 genes involved in nine sub-processes: DNA-damage response, base excision repair (BER), nucleotide excision repair, mismatch repair, non-homologous end-joining, homologous recombinational repair (HRR), RecQ helicase activities (RECQ), telomere functioning and mitochondrial DNA processes.

The study population was 1089 long-lived and 736 middle-aged Danes. A self-contained set-based test of all SNPs displayed association with longevity, supporting that the overall pathway could affect longevity. Investigation of the nine sub-processes [indicated] that BER, HRR and RECQ associated stronger with longevity than the respective remaining genes of the pathway. For HRR and RECQ, only one gene contributed to the significance, whereas for BER several genes contributed. These associations did, however, generally not pass correction for multiple testing. Still, these findings indicate that, of the entire pathway, variation in BER might influence longevity the most. These [results] were not replicated in a German sample. This might, though, be due to differences in genotyping procedures and investigated SNPs, potentially inducing differences in the coverage of gene regions. Specifically, five genes were not covered at all in the German data. Therefore, investigations in additional study populations are needed before final conclusion can be drawn.

Thursday, February 13, 2014

Multiple sclerosis (MS) is one of a number of diseases related to accelerated loss of the myelin sheathing of nerves. This loss occurs in everyone to a much lesser degree during aging - there are many medical conditions that, once you look into the mechanisms, turn out be the consequences of an acceleration of a universal process. So we should keep an eye on work aimed at the regeneration of myelin, as it may have broader applications than treating MS:

Researchers have found a "potentially novel therapeutic target" to reduce the rate of deterioration and to promote growth of brain cells damaged by multiple sclerosis (MS). A small protein that can be targeted to promote repair of damaged tissue, with therapeutic potential. The molecule, Endothelin-1 (ET-1), is shown to inhibit repair of myelin. Myelin damage is a hallmark characteristic of MS. The study demonstrates that blocking ET-1 pharmacologically or using a genetic approach could promote myelin repair.

Repair of damaged MS plaques is carried out by endogenous oliogdendrocyte progenitor cells (OPCs) in a process called remyelination. Current MS therapy can be effective in patients with relapsing and remitting MS, but "have little impact in promoting remyelination in tissue." Several studies have shown that OPCs fail to differentiate in chronic MS lesions.

Targeting ET-1 is a process that involves identifying signals in cells that could promote lesion repair. "We demonstrate that ET-1 drastically reduces the rate of remyelination. [It] is potentially a therapeutic target to promote lesion repair in deymyelinated tissue [and] could play a crucial role in preventing normal myelination in MS and in other demyelinating diseases."

Friday, February 14, 2014

Cytomegalovirus, CMV, is thought to be one of the causes of the immune system's dysfunction with age. It is a persistent herpesvirus: it cannot be effectively cleared from the body, but the immune system devotes ever more of its limited capacity to fighting it, reducing its ability to deal with new threads. This is characterized by an increase in CMV-focused memory cells. Simply getting rid of CMV, if we could, wouldn't reverse this harm: that would require a treatment along the lines of selectively destroying the CMV-specialized cells to free up space.

Infection with human cytomegalovirus (CMV) affects the function and composition of the immune system during ageing. In addition to the presence of the pathogen, the strength of the immune response, as measured by the anti-CMV IgG titre, has a significant effect on age-related pathogenesis. High anti-CMV IgG titres have been associated with increased mortality and functional impairment in the elderly. In this study, we were interested in identifying the molecular mechanisms that are associated with the strength of the anti-CMV response by examining the gene expression profiles that are associated with the level of the anti-CMV IgG titre.

The level of the anti-CMV IgG titre is associated with the expression level of 663 transcripts in nonagenarians. These transcripts and their corresponding pathways are, for the most part, associated with metabolic functions, cell development and proliferation and other basic cellular functions. However, no prominent associations with the immune system were found, and no associated transcripts were found in young controls.

The lack of defence pathways associated with the strength of the anti-CMV response can indicate that the compromised immune system can no longer defend itself against the CMV infection. Our data imply that the association between high anti-CMV IgG titres and increased mortality and frailty is mediated by basic cellular processes.

Friday, February 14, 2014

Quite varied life trajectories can emerge from evolutionary processes, not just differences in longevity between species. The older, simpler evolutionary theories of aging that only account for some of these outcomes have to be extended and refined to explain new data, and so it goes - this is science at work:

The classic evolutionary theories of aging provide the theoretical framework that has guided aging research for 60 years. Are the theories consistent with recent evidence?

At the heart of the theories lies the observation that the old count less than the young: Unfavorable traits are weeded out by evolution more slowly at higher ages; traits that are beneficial early in life are selected for despite late life costs; and resources are used to enhance reproduction at younger ages instead of maintaining the body at ages that do not matter much for evolution. The decline in the force of selection with age is viewed as the fundamental cause of aging. It is why, starting at reproductive maturity, senescence - increases in susceptibility to death and decreases in fertility - should be inevitable in all multicellular species capable of repeated breeding.

Yet, this is not the case. Increasing, constant, and decreasing mortality (and fertility) patterns are three generic variants that compose the rich diversity of life trajectories observed in nature.


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