Fight Aging! Newsletter, December 16th 2013

December 16th 2013

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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  • 3 to 1 Matching of SENS Research Donations Until Year End
  • A Few Recent Publications in Calorie Restriction Research
  • Exploring Heat Shock Proteins and Longevity Via Hormesis
  • Reviewing the Work of More of the SENS Research Foundation 2013 Interns
  • Fivefold Extension of Life Span in Nematode Worms
  • An Evolutionary Programmed Aging Viewpoint
  • Latest Headlines from Fight Aging!
    • Arguing That Mitochondrial Mutations Are Only Important to Aging in Long-Lived Species
    • Sampling the Diversity of Aging
    • More on Genetic Transposition in Aging
    • Death is Wrong: a Child's Primer on Life Extension
    • Digging in to the Biochemistry of Glucosepane
    • In Search of Drugs That Modulate Aging
    • The Potency of Exercise
    • Autophagy Required for Zebrafish Regeneration
    • Proposing Alzheimer's as a Mitochondrial Disease
    • Glycans as a Potential Biomarker of Aging


Fight Aging!, Jason Hope, and the Methuselah Foundation are matching $15,000 of donations to the SENS Research Foundation until 12/31/2013. Every $1 you donate is matched by $3, with the funds going to expand work on the foundations of tomorrow's rejuvenation therapies, treatments capable of preventing and reversing all aging-related disease and disability. Generous donors have contributed thousands of dollars in the past few weeks: thousands more are needed to hit this goal. So make your tax-deductible donation at the SENS Research Foundation website:


The practice of calorie restriction involves eating fewer calories while still obtaining optimal levels of dietary micronutrients. This results in extended healthy life spans and extended maximum life spans in near all species tested to date, though the data is currently inconclusive for primates, and it is expected that the extension of life span in long-lived animals such as humans will be much smaller than that observed in short-lived animals such as mice.

From an evolutionary perspective, the response to calorie restriction is thought to have arisen as an protective adaptation for the existence of short-lived famine conditions. The length of natural reductions in food supply due to weather, seasons, and so forth, is the same whether you are a man or a mouse - so mice evolved a comparatively long life extension (up to 40% or more) while humans are probably left with just a few additional years. If we did have the ability to extend our lives by decades through eating less, you can be certain that this would have been discovered long ago and be a well-known phenomenon.

Interestingly the effects of calorie restriction on general health and metabolism in primates and mice are very similar despite the large divergence in expected outcomes for longevity. Calorie restriction is just about the best presently available methodology for ensuring good long-term health, and the data from human studies is eye-opening. You should definitely look into it if not already practicing.

Here are some recent publications from the calorie restriction research community, just a cross-section of recent research that caught my eye while browsing. This is fairly low-level work, scientists digging into details in search of new lines of research to pursue.

What are the roles of calorie restriction and diet quality in promoting healthy longevity?

Epidemiological and experimental data indicate that diet plays a central role in the pathogenesis of many age-associated chronic diseases, and in the biology of aging itself. Data from several animal studies suggest that the degree and time of calorie restriction (CR) onset, the timing of food intake as well as diet composition, play major roles in promoting health and longevity, breaking the old dogma that only calorie intake is important in extending healthy lifespan.

Data from human studies indicate that long-term CR with adequate intake of nutrients results in several metabolic adaptations that reduce the risk of developing type 2 diabetes, hypertension, cardiovascular disease and cancer. Moreover, CR opposes the expected age-associated alterations in myocardial stiffness, autonomic function, and gene expression in the human skeletal muscle. However, it is possible that some of the beneficial effects on metabolic health are not entirely due to CR, but to the high quality diets consumed by the CR practitioners, as suggested by data collected in individuals consuming strict vegan diets.

Combined treatment of rapamycin and dietary restriction has a larger effect on the transcriptome and metabolome of liver

Rapamycin (Rapa) and dietary restriction (DR) have consistently been shown to increase lifespan. To investigate whether Rapa and DR affect similar pathways in mice, we compared the effects of feeding mice ad libitum (AL), Rapa, DR, or a combination of Rapa and DR (Rapa + DR) on the transcriptome and metabolome of the liver. The principal component analysis shows that Rapa and DR are distinct groups.

Over 2500 genes are significantly changed with either Rapa or DR when compared with mice fed AL; more than 80% are unique to DR or Rapa. A similar observation was made when genes were grouped into pathways; two-thirds of the pathways were uniquely changed by DR or Rapa. The metabolome shows an even greater difference between Rapa and DR; no metabolites in Rapa-treated mice were changed significantly from AL mice, whereas 173 metabolites were changed in the DR mice. Interestingly, the number of genes significantly changed by Rapa + DR when compared with AL is twice as large as the number of genes significantly altered by either DR or Rapa alone.

In summary, the global effects of DR or Rapa on the liver are quite different and a combination of Rapa and DR results in alterations in a large number of genes and metabolites that are not significantly changed by either manipulation alone, suggesting that a combination of DR and Rapa would be more effective in extending longevity than either treatment alone.

Thermoregulatory, cardiovascular, and metabolic responses to mild caloric restriction in the Brown Norway rat

Caloric restriction (CR) has been demonstrated to prolong the life span of a variety of species. CR-induced reduction in core temperature (Tc) is considered a key mechanism responsible for prolonging life span in rodents; however, little is known about the regulation of CR-induced hypothermia as a function of the circadian cycle. We assessed how mild CR that resulted in a 10% reduction in body weight affected the 24 h patterns of Tc as well as heart rate (HR) and motor activity (MA) of the Brown Norway rat.

Telemetered rats were allowed to feed for 20 weeks ad libitum (AL) or given a CR diet. Tc, HR, and MA of CR rats exhibited nocturnal reductions and diurnal elevations, opposite to that of AL rats. The effects of CR appeared to peak at ~4 weeks. Metabolic rate (MR) and respiratory exchange ratio (RER) were measured overnight after 18 weeks of CR. MR and RER were elevated markedly at the time of feeding in CR rats and then declined during the night.

We found that the pattern of Tc was altered with CR, characterized by elimination of high nocturnal Tc's typically observed in AL animals. In terms of mechanisms to prolong life span in CR animals, we suggest that the shift in the pattern of Tc during CR (i.e., elimination of high Tc's) may be as critical as the overall mean reduction in Tc. Future studies should address how the time of feeding may affect the thermoregulatory response in calorically restricted rats.

Calorie restriction attenuates lipopolysaccharide (LPS)-induced microglial activation in discrete regions of the hypothalamus and the subfornical organ

Calorie restriction (CR) has been shown to increase longevity and elicit many health promoting benefits including delaying immunosenescence and attenuating neurodegeneration in animal models of Alzheimer's disease and Parkinson's disease. CR also suppresses microglial activation following cortical injury and aging.

We previously demonstrated that CR attenuates lipopolysaccharide (LPS)-induced fever and shifts hypothalamic signaling pathways to an anti-inflammatory bias. The current study investigated regional changes in LPS-induced microglial activation in mice exposed to 50% CR for 28 days. Exposure to CR attenuated LPS-induced fever, and LPS-induced microglial activation in a subset of regions [and] microglial activation [was] positively correlated with body temperature.

These data suggest that CR exerts effects on regionally specific populations of microglia; particularly, in appetite-sensing regions of the hypothalamus, and/or regions lacking a complete blood brain barrier, possibly through altered pro- and anti-inflammatory signaling in these regions.


Many mild forms of environmental stress extend healthy life in laboratory species: yeast, flies, worms, and mice. None of the really interesting processes are fully understood at this point, but enough has been learned to think that there are numerous overlapping mechanisms involved. Thus we should expect to see that there is at least some overlap in the biochemical details of responses to calorie restriction, mild heat stress, exercise, and others including low toxin doses, despite the fact that they overall produce what look to be very different shifts in metabolism.

The activity of heat shock proteins is one shared mechanism seen in a number of different forms of life extension. As the name might imply these are proteins first cataloged in connection with the metabolic response to excessive heat, but they also turn out for cold, oxygen deprivation, and some other circumstances that stress cells. Heat shock proteins play a role in cellular housekeeping, helping to prevent harmful accumulations of misfolded proteins, among other tasks.

Hormesis is the name given to circumstances whereby beneficial results occur as a result of mild levels of damage and stress. Some of the benefit of calorie restriction, exercise, and so forth, arises due to the triggering of hormetic processes: a little damage spurs all sorts of cellular maintenance for an extended time, resulting in a net gain in integrity and less damage than would otherwise exist. Extended healthy longevity is the observable result. Heat shock proteins are just one of the mechanisms involved here - there are numerous others.

In the near future I imagine that some fraction of the researchers presently investigating drugs that might slow aging will move on to try to produce pharmaceutical means to trigger the beneficial side of hormesis. This seems like a plausible goal, especially in the case of heat shock proteins, given what is known today, but there doesn't seem to be a great deal of movement in this direction at the present time.

Here are a couple of recent papers from research groups looking into the mechanisms and connections associated with heat shock proteins and their effect on aging and longevity.

The long-term effects of a life-prolonging heat treatment on the Drosophila melanogaster transcriptome suggest that heat shock proteins extend lifespan

Heat-induced hormesis, i.e. the beneficial effect of mild heat-induced stress, increases the average lifespan of many organisms. This effect, which depends on the heat shock factor, [decreases] mortality rate weeks after the stress has ceased. To identify candidate genes that mediate this lifespan-prolonging effect late in life, we treated flies with mild heat stress (34°C for 2 hours) 3 times early in life and compared the transcriptomic response in these flies versus non-heat-treated controls 10-51 days after the last heat treatment.

We found significant transcriptomic changes in the heat-treated flies. Several hsp70 probe sets were up-regulated 1.7-2-fold in the mildly stressed flies weeks after the last heat treatment. This result was unexpected as the major Drosophila heat shock protein, Hsp70, is reported to return to normal levels of expression shortly after heat stress. We conclude that the heat shock response, and Hsp70 in particular, may be central to the heat-induced increase in the average lifespan in flies that are exposed to mild heat stress early in life.

Integrin-linked kinase modulates longevity and thermotolerance in C. elegans through neuronal control of HSF-1

Integrin-signaling complexes play important roles in cytoskeletal organization and cell adhesion in many species. Components of the integrin-signaling complex have been linked to aging in both Caenorhabditis elegans and Drosophila melanogaster, but the mechanisms underlying this function are unknown.

Here, we investigated the role of integrin-linked kinase (ILK), a key component of the integrin-signaling complex, in lifespan determination. We report that genetic reduction of ILK in both C. elegans and Drosophila increased resistance to heat stress, and led to lifespan extension in C. elegans without majorly affecting cytoskeletal integrity. In C. elegans, longevity and thermotolerance induced by ILK depletion was mediated by the heat-shock factor-1 (HSF-1), a major transcriptional regulator of the heat-shock response (HSR).


The SENS Research Foundation is the leading coordinator of rejuvenation research: funding and organizing scientific programs with the aim of reversing degenerative aging and preventing age-related disease. This can be achieved through the development of biotechnologies capable of repairing the identified forms of cellular and molecular damage that cause aging. Some of these biotechnologies are within just a few years of proof of concept treatments deployed in the laboratory, given fully funded research programs. Sufficient resources for such rapid progress are lacking, however: rejuvenation research of this sort is entirely funded by philanthropy at the present time, ignored by more mainstream sources of research funding.

One of the programs run by the SENS Research Foundation assembles talented young graduate researchers from around the world each year, offering them the chance to further their careers in the molecular biology of aging and longevity by performing cutting-edge research at the Foundation's research center, or in allied laboratories also focused on aging. We are all still aging today, and the researchers who lead the deployment of the first generation of clinical rejuvenation treatments will not be those presently at the peak of their careers. Creating the next generation of the research community is just as important as persuading the present generation to focus on repair-based approaches to treating aging.

Still, much can be accomplished with comparatively little nowadays. The state of biotechnology today is very different from that of even just ten or twenty years ago: tasks that would have required a fully staffed institution and tens of millions of dollars - if they were even possible at all - can now be achieved by a single researcher and tens of thousands of dollars. The cost of life science research is plummeting, even as the capabilities of laboratory technologies expand just as rapidly.

The SENS Research Foundation has been showing off the work of the 2013 interns over the past few months:

  • A Spotlight on SENS Research Foundation Interns
  • Another Spotlight on SENS Research Foundation Interns

Here is the latest installment of posts:

Evidence that Cell Senescence is a Factor in Chronic Obstructive Pulmonary Disease -- SRF intern Shahar Bracha

Chronic obstructive pulmonary disease (COPD) is a lung disease which is currently the 4th leading cause of death in the world, affecting the lives of hundreds of millions every year. In this disease, an excessive inflammatory response to noxious particles or gases causes airflow to become restricted. A deadly combination of chronic inflammation in the small airways and destruction of the alveoli slowly limits the lungs' ability to do their job transmitting oxygen to the blood.

The two main risk factors for COPD are smoking and age. Senescence of cells in the airway due to environmental stress, such as smoking, or due to advanced age may explain these risk factors. Senescence is a non-proliferative state which a normal, dividing cell may enter to prevent excessive cell growth. Although the senescent response limits tumorigenesis in these cells, it may also contribute to the pathogenesis of COPD by both limiting the proliferative capacity necessary for tissue repair and by promoting chronic inflammation.

To determine if senescence plays a role in COPD, I studied transgenic mice that possessed lung cells with an impaired ability to undergo senescence. The senescence-impaired cells are a special type of epithelial cell found in small airways in the lungs, called Clara cells. By inactivating the tumor suppressor gene p53 in these cells, one of the main regulatory pathways of cellular senescence was impaired. I also developed a protocol for inducing COPD-like symptoms by treating the mice with aerosolized lipopolysaccharide (LPS). This allowed me to compare the response of these transgenic mice to normal mice when faced with COPD-inducing conditions. The correlation between fewer senescent cells and lower levels of inflammation suggests that the senescence of Clara cells indeed might play an important role in the pathogenesis of COPD. Further study of the role senescence plays in the pathogenesis of COPD could reveal new targets for COPD therapies.

A Study of the Effect of Histone Acetylation on ATM Activation and the SASP by SRF Intern Meredith Giblin

Cellular senescence is a process in which a cell ceases to proliferate in response to oncogenic stimuli. Ironically, although senescence helps protect the cell in question from becoming cancerous, the senescence-associated secretory phenotype (SASP) has been shown to contribute to age-related diseases, in particular cancer. The Campisi lab has previously demonstrated that several proteins involved in the DNA damage response (DDR) pathway are also necessary for the SASP. Inhibition of histone deacetylases (HDACs) and activation of the ataxia telangiectasia mutated (ATM) protein in turn activate the SASP. This suggests that the state of the chromatin rather than the physical breaks in DNA is responsible for initiating the SASP response in senescent cells. My project sought to characterize the role specific HDACs play in ATM activation and SASP induction.

Investigating the Mechanism of Lithium Treatment of a Parkinson's Disease Model with SRF Intern Sean Batir

Previous research in Dr. Anderson's laboratory revealed that lithium, a drug commonly used to treat bipolar disorder, also may prevent neurodegeneration in an animal model of Parkinson's disease. Working with postdoctoral researcher Dr. Christopher Lieu, I tried to determine what molecular pathway is associated with the previously observed effects of lithium on the symptoms of a Parkinson's disease animal model.

Two possible mechanisms were investigated: autophagy (the process by which a cell can recycle and remove metabolic cellular debris, protein aggregates, and damaged organelles) and inflammation. One theory argues that dysfunction in the neurocellular autophagy pathway is responsible for the neuronal degeneration and resulting loss of motor control observed in Parkinson's disease. If so, reactivation of the autophagy mechanism may be responsible for the neuroprotective properties of lithium in a Parkinson's disease model. We also tested the possibility that the neuroprotective properties of lithium may be a result of lithium's effect on neuronal inflammation.

Inhibition of Breast Cancer Cell Metastasis by SRF Intern Eric Zluhan

Actin fibers are a key component of the proteolytic invadopodia used by breast cancer cells during metastasis. A formin protein known as FMNL1 plays a crucial role in actin assembly during macrophage migration and has been implicated in proteolytic invadopodia as well. My summer project tested whether or not inhibition of FMNL1 function in breast cancer cells [would] limit their metastatic capabilities.

I attempted to lower FMNL1 protein levels [in] cells by using a process known as RNA interference (RNAi), a technique that can be used to selectively remove a specific RNA transcript from cells. Once I confirmed that FMNL1 protein levels were reduced, I tested the invasive capability of the cells. RNAi-treated cells were placed on an artificial basement membrane, and I measured the number of cells that were able to move through the membrane. Fewer FMNL1 siRNA-treated cells were able to penetrate the membrane compared to cells treated with a control siRNA construct.


The next logical step for researchers after discovering a range of different ways to slow aging in laboratory animals is to try these methodologies in combination. Many in fact work to extend healthy life through overlapping mechanisms, and so much of the incentive for the researchers is not in fact to produce greater extension of longevity, but rather to get a better handle on which of these methods of life extension are just different ways of triggering the same underlying processes.

Some years ago, researchers demonstrated a tenfold increase in life span in nematode worms. Short-lived lower animals have so far shown a much greater potential extension of life than longer-lived higher animals; for example the record in mice is only a 60-70% extension of life span, even though very similar approaches are presently used to alter metabolism to enhance longevity in species such as worms, flies, and mice. In humans we'd expect the benefits to be much smaller again: the equivalent natural mutants in human populations don't appear to live longer than the rest of us, although studies suggest that they are more resistant to some age-related disease.

That tenfold increase in nematode life spans was achieved through a single gene mutation in the insulin / insulin-like growth factor 1 pathway. Here, however researchers achieve a fivefold increase by combining methods that individually produce smaller gains:

Five-Fold Lifespan Extension in C. Elegans by Combining Mutants

What are the limits to longevity? New research in simple animals suggests that combining mutants can lead to radical lifespan extension. [Scientists] combined mutations in two pathways well-known for lifespan extension and report a synergistic five-fold extension of longevity in the nematode C. elegans.

The mutations inhibited key molecules involved in insulin signaling (IIS) and the nutrient signaling pathway Target of Rapamycin (TOR). Single mutations in TOR usually result in a 30 percent lifespan extension, while mutations in IIS (Daf-2) often result in a doubling of lifespan in the worms - added together they would be expected to extend longevity by 130 percent. "Instead, what we have here is a synergistic five-fold increase in lifespan. The two mutations set off a positive feedback loop in specific tissues that amplified lifespan."

The positive feedback loop (DAF-16 via the AMPK complex) originated in the germline tissue of worms. The germline is a sequence of reproductive cells that may be passed onto successive generations. "The germline was the key tissue for the synergistic gain in longevity - we think it may be where the interactions between the two mutations are integrated. The finding has implications for similar synergy between the two pathways in more complex organisms."

The germline connection is interesting, as other researchers have shown that life can be extended in nematodes via removal of the germline, or genetic manipulations primarily focused on germline cells.

These pioneering demonstrations of life extension in the laboratory by slowing aging have, I think, little direct relevance to the future of human life extension. They are principally important for the continued accumulation of knowledge regarding metabolism and aging. Development of means to slow aging in humans isn't a good path from a practical point of view: it is very challenging, very expensive, and the safe adjustment of metabolism will require far more knowledge than is presently available to the research community, even when the goal is only to replicate known beneficial metabolic alterations such as the response to exercise or calorie restriction. The result at the end of the day - therapies to slow the course of aging - will be of little use to old people, despite the fantastic cost it will require to get to that point.

This is why it is important to look past much of this work on slowing aging, and the media attention it obtains, and focus instead on repair-based strategies such as SENS research. We will only be able to meaningfully help the aged - ourselves in a few decades, in other words - by developing rejuvenation therapies, not just means to slightly slow down the aging process. To rejuvenate the old, to reverse aging, requires a focus on repair of the known and cataloged forms of damage that cause degeneration: the research community can do that with the metabolism we have, with no need to engineer a new one. Further, far more is known of what has to be done than is the case for the metabolic manipulation approach to slow aging.


Josh Mitteldorf blogs fairly regularly on the topic of aging and longevity science. I believe that he and I are on much the same page when it comes to the necessity for greater funding and more rapid progress towards therapies to treat degenerative aging, and the plausibility of achieving radical life extension through medical technology. When it comes to the details of how to proceed, however, we are at opposite ends of the pool. Based on my reading of the field, I see aging as accumulated damage and the reactions to that damage, which means that SENS-like research focused on damage repair is the way to create rejuvenation. Mitteldorf, on the other hand, sees aging as a genetic program that creates damage. In his view damage repair will be ineffectual, and the research community should focus on adjusting the operation of metabolism such that its epigenetic patterns are restored to youthful levels - reversing the program, in other words. So he is in favor of the expansion of programs such as work on drugs to change TOR signaling, for example.

The types of life extension research that the two of us back couldn't be more different, and the predicted outcomes stand in opposition to one another. To a programmed aging advocate damage repair is a slow road to nowhere, while the aging as damage camp in turn see manipulation of metabolism and epigenetic patterns as a slow road to marginal treatments. Interestingly, the mainstream of the research community largely holds an aging as damage consensus, but they also largely work on ways to slow aging through metabolic manipulation, rather than aiming for damage repair. This I blame on the costly and extensive regulations associated with medical research and clinical application of medicine: if your work isn't a drug that can be targeted to a specific named disease, then getting it approved for use will be somewhere between an exceedingly expensive uphill battle and impossible. This reality is recognized and percolates back up the research chain to make it very hard to raise funding for even early stage research into anything that is new, radical, and different.

In any case, I see the programmed aging view as interesting but wrong. Everyone in the community, whether hypothesizing programmed aging or aging as damage, largely agrees on the facts in evidence, the differences between old and young tissue and other data. The interpretation of those facts is where the action is. Mitteldorf's views are similar in some ways but also a little different from those of the Russian gerontology community I've pointed out in past posts, and so seem worth reading through.

The Selfish Gene vs Multi-level Selection: Aging Doesn't Fit

Genes are evolved to promote their own replication, and also copies of themselves that exist in relatives. In the 1970s, the theory was extended by George Price to deal rigorously with groups that may or may not be related. This is now known as multi-level selection (MLS). There is an ongoing dialog in the evolutionary community about whether MLS is significant in nature, which is still the minority view. The majority continues to hold that everything should be explainable in terms of the selfish gene.

But aging cannot be explained by the selfish gene; and even with the considerably broader perspective of MLS, the evolution of aging remains problematic. What is missing from both systems is ecology. When species' interdependence is taken into account, it becomes possible to understand aging and many other cases where individuals sacrifice their own fitness to the community.

The Selfish Gene can't explain aging - but neither can Multi-level Selection

Last week, I discussed the gene-eyed view of evolution that came to dominate evolutionary theory of the 20th century. In the 1960s, this view hardened into a dogma, and provoked a reaction, in recognition of the many cooperative networks in nature that are difficult to explain in terms of "kin selection," the only recourse of the Selfish Gene.

I continue [here] with the science of multilevel selection (MLS), and talk about why aging is a tough nut to crack. Clearly the selfish gene paradigm is inadequate to explain aging. MLS provides a formal test for deciding whether a given trait can evolve via group selection, and according to these criteria, aging should not be able to evolve.

Where do we go from here? What is missing from both systems is ecology. When species' interdependence is taken into account, it becomes possible to understand aging and many other cases where individuals sacrifice their own fitness to the community.


Monday, December 9, 2013

Researchers here produce models to argue that the role of accumulating mitochondrial mutations in aging can only play out significantly in long-lived species. If this in fact turns out to the be the case it would be a hindrance to efforts to develop mitochondrial repair technologies as a rejuvenation therapy, as they would have little effect in laboratory mice. That would make it harder to drum up the enthusiasm to proceed further towards clinical applications.

The fastest way to find out whether the models presented in this paper actually reflect reality is to develop a working implementation of mitochondrial DNA (mtDNA) repair, but like many areas of research that are potentially applicable to extending healthy life there is comparatively little funding for this sort of work. With much greater funding, an actual implementation is only a few years away.

The mitochondrial theory of ageing is one of the main contenders to explain the biochemical basis of the ageing process. An important line of support comes from the observation that mtDNA deletions accumulate over the life course in post-mitotic cells of many species. A single mutant expands clonally and finally replaces the wild-type population of a whole cell.

One proposal to explain the driving force behind this accumulation states that the reduced size leads to a shorter replication time, which provides a selection advantage. However, this idea has been questioned on the grounds that the mitochondrial half-life is much longer than the replication time, so that the latter cannot be a rate limiting step. To clarify this question, we modelled this process mathematically and performed extensive deterministic and stochastic computer simulations to study the effects of replication time, mitochondrial half-life and deletion size.

Our study shows that the shorter size does in principle provide a selection advantage, which can lead to an accumulation of the deletion mutant. However, this selection advantage diminishes the shorter is the replication time of wt mtDNA in relation to its half-life. Using generally accepted literature values, the resulting time frame for the accumulation of mutant mtDNAs is only compatible with the ageing process in very long lived species like humans, but could not reasonably explain ageing in short lived species like mice and rats.

There are proposals for other mechanisms to explain how damaged mitochondria can overtake cells and replace the undamaged type: for example, through greater resistance to being cleared out by quality control mechanisms such as mitophagy.

Monday, December 9, 2013

Aging can be defined as a rise over time in mortality rate due to intrinsic causes. This doesn't tell us much about what exactly might be happening under the hood, beyond a general failure in function, but it has proven to be a useful working definition for a broad range of research. Not all species exhibit this rise in mortality rate, however:

Not all species weaken and become more likely to die as they age. Some species get stronger and less likely to die with age, while others are not affected by age at all. Increasing weakness with age is not a law of nature. [Researchers] have studied ageing in 46 very different species including mammals, plants, fungi and algae, and they surprisingly find that there is a huge diversity in how different organisms age. Some become weaker with age - this applies to e.g. humans, other mammals, and birds; others become stronger with age - this applies to e.g. tortoises and certain trees, and others become neither weaker nor stronger - this applies to e.g. Hydra, a freshwater polyp.

While there is plenty of scientific data on ageing in mammals and birds, there is only sparse and incomplete data on ageing in other groups of vertebrates, and most invertebrates, plants, algae, and fungi. For several species mortality increases with age - as expected by evolutionary scientists. This pattern is seen in most mammal species including humans and killer whales, but also in invertebrates like water fleas. However, other species experience a decrease in mortality as they age, and in some cases mortality drops all the way up to death. This applies to species like the desert tortoise (Gopherus agassizii) which experiences the highest mortality early on in life and a steadily declining mortality as it ages. Many plant species, e.g. the white mangrove tree (Avicennia marina) follow the same pattern.

Amazingly, there are also species that have constant mortality and remain unaffected by the ageing process. This is most striking in the freshwater polyp Hydra magnipapillata which has constant low mortality. In fact, in lab conditions, it has such a low risk of dying at any time in its life that it is effectively immortal. "Extrapolation from laboratory data show that even after 1400 years five per cent of a hydra population kept in these conditions would still be alive."

Tuesday, December 10, 2013

Some researchers believe that transposable elements in DNA are involved in the aging process, though definitive links to damage or dysfunction are presently lacking. The behavior certainly changes with increasing age, however:

Transposable elements (TEs) were discovered [in] maize and have since been found to be ubiquitous in all living organisms. Transposition is mutagenic and organisms have evolved mechanisms to repress the activity of their endogenous TEs. Transposition in somatic cells is very low, but recent evidence suggests that it may be derepressed in some cases, such as cancer development.

We have found that during normal aging several families of retrotransposable elements (RTEs) start being transcribed in mouse tissues. In advanced age the expression culminates in active transposition. These processes are counteracted by calorie restriction (CR), an intervention that slows down aging. Retrotransposition is also activated in age-associated, naturally occurring cancers in the mouse. We suggest that somatic retrotransposition is a hitherto unappreciated aging process. Mobilization of RTEs is likely to be an important contributor to the progressive dysfunction of aging cells.

Tuesday, December 10, 2013

Crafting short illustrated books to explain the straightforward views of the life extension community seems like a good idea, and not just for an audience of younger children. The people who will most likely be leading the deployment of the first practical technologies of rejuvenation - in laboratories, in young companies - are in their teens and twenties today, with time enough to choose other paths instead:

If you have ever asked, "Why do people have to die?" then this book is for you. The answer is that no, death is not necessary, inevitable, or good. In fact, death is wrong. Death is the enemy of us all, to be fought with medicine, science, and technology. This book introduces you to the greatest, most challenging, most revolutionary movement to radically extend human lifespans so that you might not have to die at all.

You will learn about some amazingly long-lived plants and animals, recent scientific discoveries that point the way toward lengthening lifespans in humans, and simple, powerful arguments that can overcome the common excuses for death. If you have ever thought that death is unjust and should be defeated, you are not alone. Read this book, and become part of the most important quest in human history. It is here to show you that, no matter who you are and what you can do, there is always a way for you to help in humanity's struggle against death.

Wednesday, December 11, 2013

Advanced glycation end-products (AGEs) are forms of waste produced by the ordinary operation of metabolism, in which sugars attach to proteins to form hardy compounds that in some cases are a challenge to remove. In humans glucosepane is by far the most prevalent form of AGE, and its growing presence with age causes increased levels of chronic inflammation, and a loss of elasticity and function in many tissues.

Very few researchers are presently working on ways to remove glucosepane, which is why the SENS Research Foundation funds a program aimed at making progress towards this goal. A therapy to clear glucosepane would remove this contribution to degenerative aging, and is thus a needed part of any future toolkit of rejuvenation treatments.

Ageing and diabetes share a common deleterious phenomenon, the formation of Advanced Glycation Endproducts (AGEs), which accumulate predominantly in collagen due to its low turnover. Though the general picture of glycation has been identified, the detailed knowledge of which collagen amino acids are involved in AGEs is still missing. In this work we use an atomistic model of a collagen fibril to pinpoint, for the first time, the precise location of amino acids involved in the most relevant AGE, glucosepane.

The results show that there are 14 specific lysine-arginine pairs that, due to their relative position and configuration, are likely to form glucosepane. We find that several residues involved in AGE crosslinks are within key collagen domains, such as binding sites for integrins, proteoglycans and collagenase, hence providing molecular-level explanations of previous experimental results showing decreased collagen affinity for key molecules. Altogether, these findings reveal the molecular mechanism by which glycation affects the biological properties of collagen tissues, which in turn contribute to age- and diabetes-related pathological states.

Wednesday, December 11, 2013

Where the mainstream of aging research is thinking about extending healthy life, these researchers are near entirely focused on traditional drug discovery and development with the aim of gently slowing the rate of aging. This will no doubt result in a great deal of new knowledge in the course of better understanding the molecular biology of nature means of life extension, such as calorie restriction, but it doesn't stand much of a chance of producing technologies that will allow you and I to live significantly longer. A drug to slightly slow aging that emerges 20 years from now will of little use to people already old, and only of marginal use for everyone else.

An important task to undertake today is convincing the mainstream of aging research to adopt the SENS view on aging: to work on rejuvenation therapies that repair the known underlying damage of aging, a much more effective approach that will result in treatments that do help the elderly and do significantly extend healthy life spans.

Once a backwater in medical sciences, aging research has emerged and now threatens to take the forefront. This dramatic change of stature is driven from 3 major events. First and foremost, the world is rapidly getting old. Never before have we lived in a demographic environment like today, and the trends will continue such that 20% percent of the global population of 9 billion will be over the age of 60 by 2050. Given current trends of sharply increasing chronic disease incidence, economic disaster from the impending silver tsunami may be ahead.

A second major driver on the rise is the dramatic progress that aging research has made using invertebrate models such as worms, flies, and yeast. Genetic approaches using these organisms have led to hundreds of aging genes and, perhaps surprisingly, strong evidence of evolutionary conservation among longevity pathways between disparate species, including mammals. Current studies suggest that this conservation may extend to humans.

Finally, small molecules such as rapamycin and resveratrol have been identified that slow aging in model organisms, although only rapamycin to date impacts longevity in mice. The potential now exists to delay human aging, whether it is through known classes of small molecules or a plethora of emerging ones. But how can a drug that slows aging become approved and make it to market when aging is not defined as a disease? Here, we discuss the strategies to translate discoveries from aging research into drugs. Will aging research lead to novel therapies toward chronic disease, prevention of disease or be targeted directly at extending lifespan?

Thursday, December 12, 2013

Exercise and calorie restriction provide greater beneficial effects than much of the array of therapies making up modern medicine; this is a measure of just how much work is left to do in medical research. There remain many conditions for which only marginal, palliative treatments exist. It is a strange era we live in: that this can be the case on the one hand, and yet on the other the research community is just a few decades away from being able to cure all cancer, grow organs from a patient's cells, and create rejuvenation therapies that will greatly extend healthy life.

To determine the comparative effectiveness of exercise versus drug interventions on mortality outcomes [we] combined study level death outcomes from exercise and drug trials using random effects network meta-analysis.

We included 16 (four exercise and 12 drug) meta-analyses. Incorporating an additional three recent exercise trials, our review collectively included 305 randomised controlled trials with 339,274 participants. Across all four conditions with evidence on the effectiveness of exercise on mortality outcomes (secondary prevention of coronary heart disease, rehabilitation of stroke, treatment of heart failure, prevention of diabetes), 14,716 participants were randomised to physical activity interventions in 57 trials.

No statistically detectable differences were evident between exercise and drug interventions in the secondary prevention of coronary heart disease and prediabetes. Physical activity interventions were more effective than drug treatment among patients with stroke. Diuretics were more effective than exercise in heart failure. Inconsistency between direct and indirect comparisons was not significant.

Although limited in quantity, existing randomised trial evidence on exercise interventions suggests that exercise and many drug interventions are often potentially similar in terms of their mortality benefits.

Thursday, December 12, 2013

Zebrafish are studied for their exceptional regenerative capacity, as researchers are attempting to determine whether we mammals have similar, dormant abilities to regenerate limbs and organs, or whether there is any other way to port this ability into human tissues. The first step on this path is to catalog the molecular biology of zebrafish regeneration: how exactly it works under the hood. This research is a part of these efforts:

Regeneration is the ability of multicellular organisms to replace damaged tissues and regrow lost body parts. This process relies on cell fate transformation that involves changes in gene expression as well as in the composition of the cytoplasmic compartment, and exhibits a characteristic age-related decline. Here, we present evidence that genetic and pharmacological inhibition of autophagy - a lysosome-mediated self-degradation process of eukaryotic cells, which has been implicated in extensive cellular remodelling and aging - impairs the regeneration of amputated caudal fins in the zebrafish. Thus, autophagy is required for injury-induced tissue renewal.

We further show that upregulation of autophagy in the regeneration zone occurs downstream of mitogen-activated protein kinase/extracellular signal-regulated kinase signalling to protect cells from undergoing apoptosis and enable cytosolic restructuring underlying terminal cell fate determination. This novel cellular function of the autophagic process in regeneration implies that the role of cellular self-digestion in differentiation and tissue patterning is more fundamental than previously thought.

Friday, December 13, 2013

This is an interesting viewpoint on the underlying causes of Alzheimer's disease, but one with little to no support in the research community at the present time. They are not the only group to think that removing beta amyloid will do little to address Alzheimer's symptoms, however, and there has been a shift in recent years to begin to focus on amyloid precursor protein instead:

Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains that gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Aβ) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it.

We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts that biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aβ at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it.

Friday, December 13, 2013

Researchers here uncover a set of characteristic molecular changes that correlate well with chronological and biological age. This is not the only such discovery in recent years: DNA methylation patterns are another candidate for biomarker of aging, and it may yet be the case that some form of telomere measurement might also do the job. It is important to have a good way to measure biological age, how damaged an individual is, as how else is the research community to effectively evaluate the first generation of prospective rejuvenation treatments when they arrive? The wait and see approach of life span studies is already far too expensive in time and money when carried out in laboratory mice, and certainly impractical in humans on an ongoing basis.

Fine structural details of glycans attached to the conserved N-glycosylation site significantly not only affect function of individual immunoglobulin G (IgG) molecules but also mediate inflammation at the systemic level.

By analyzing IgG glycosylation in 5,117 individuals from four European populations, we have revealed very complex patterns of changes in IgG glycosylation with age. Several IgG glycans (including FA2B, FA2G2, and FA2BG2) changed considerably with age and the combination of these three glycans can explain up to 58% of variance in chronological age, significantly more than other markers of biological age like telomere lengths. The remaining variance in these glycans strongly correlated with physiological parameters associated with biological age.

Thus, IgG glycosylation appears to be closely linked with both chronological and biological ages. Considering the important role of IgG glycans in inflammation, and because the observed changes with age promote inflammation, changes in IgG glycosylation also seem to represent a factor contributing to aging.


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