FIGHT AGING! NEWSLETTER
September 30th 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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- Longecity: Help Raise Funds For a Rejuvenation Research Project Carried Out By a SENS Research Foundation Team
- Investigating SIRT3 as a Target for Calorie Restriction Mimetic Development
- An Extremely Suspicious Looking Technology: QUEC PHISIS TM
- Scenarios for the Near Future of Human Longevity
- The Last Generation to Die
- Latest Headlines from Fight Aging!
- FGT-1 Knockdown Extends Life in Nematode Worms
- Towards a Stem Cell Therapy for Periodontitis
- A Study of Metabolism and Lifelong Calorie Restriction in Dogs
- TFAM, Aging, and Calorie Restriction
- A Demonstration of Reduced Age-Related Hearing Loss in Mice
- A Measure of the Degree to Which Telomere Length is Inherited
- The Prospects for Therapies Based on Heterochronic Plasma Exchange
- Autoantibody Mechanisms as a Basis for Therapies to Clear Senescent Cells
- Cellular Senescence and Its Relationship With Cancer
- Exploring the Role of Natural Antioxidants Inside Mitochondria
LONGECITY: HELP RAISE FUNDS FOR A REJUVENATION RESEARCH PROJECT CARRIED OUT BY A SENS RESEARCH FOUNDATION TEAM
As I'm sure you're aware, the Longecity community raises funds for modestly-sized research projects in longevity science: things that can be accomplished for a few tens of thousands of dollars and in six months to a year. In this day and age that encompasses a lot of useful, cutting edge research if you can find a group with access to an established laboratory - biotechnology costs are a fraction of what they were even a decade ago, and a single postgraduate student can achieve today what would have required an entire dedicated laboratory staff in the 1990s. For example in 2012 Longecity funded a study on transplantation of young microglia into old mice to see if this can help to slow or reverse age-related neurodegeneration.
Here is an even better goal for 2013: funding a stepping stone project for mitochondrial repair carried out by a SENS Research Foundation team. Mitochondrial damage is one of the root causes of degenerative aging, and the SENS Research Foundation is the leading coordinator of scientific work aimed at doing something about this. The funding deadline is November 28th, and Longecity will provide $2 to the project for every $1 donated by folk such as you and I:
LongeCity Research Support 2013: Mitochondrial Gene Therapy
After careful consideration of a very competitive round this year, we are delighted to have identified a research team and project that we can warmly recommend for community funding:
Development of an Innovative Gene Therapy Method to Cure Mitochondrial Aging - "Backing Up" the Mitochondrial Genome
Mitochondria, the power plants of the cell, contain their own DNA. Unlike the nucleus, mitochondria lack an efficient system to repair damaged DNA, and this damage accumulates over time. As we age, these accumulated mutations result in an increase in oxidative stress throughout the body. It is no coincidence that organisms which age more slowly consistently display lower rates of mitochondrial free radical damage. Reversing and/or preventing damage to mitochondrial DNA may be a key factor in slowing the aging process.
In this project, engineered mitochondrial genes will be used to restore function to cells that contain defective mitochondrial genes.
The SENS team is developing a unique method for targeting these genes to the mitochondria; this step has been the bottleneck in research on this topic over the last decade. In their system, the mRNA from the engineered mitochondrial gene is targeted to the mitochondrial surface before it is translated into a protein using a co-translation import strategy. Once imported, it is incorporated into the correct location in the inner mitochondrial membrane. The long-term goal of this project is to utilize this improved targeting strategy to rescue mutated mitochondrial DNA and thereby prevent and cure one of the major causes of cellular aging.
The research brief is available to logged in Longecity members, but you can download a PDF copy here if you want to take a look at the details. This is a small but valuable project within the larger SENS strategy for dealing with the contribution of mitochondrial damage to aging. In the future a great deal of science will look this way: more effort made to break down long-term research plans into goals that can be crowdfunded easily in a step by step fashion.
Our six month goal is two-fold. First, we will create cells that are null for two mitochondrial genes: CyB and ATP8. Second, we will "cure" the cells by inserting engineered versions of CyB and ATP8 into the nuclear genome, rather than the mitochondrial genome, and then target the functional protein into the mitochondria.
We are requesting a budget of $21,000 to pay for the supplies necessary to continue this project. We have a talented team of highly trained mitochondrial biologists working on mitoSENS. Right now the rate-limiting factor is the cost of the expensive reagents that we use for these experiments. Increasing our funding will allow us to double the pace of our research and bring results to the public much faster. Two areas which are costly are reagents for operating our qPCR machine and for culturing our mutant cells. The bulk of the money will be spent on reagents for those two types of work. Additionally, valuable hours are spent manually counting cells under a microscope, and the purchase of an automated cell counter would speed up this work significantly and would provide a lasting contribution to lab efficiency.
You can pose questions to the researcher at the Longecity forums, and donate at the site. The present goal for community donations is $7,000, with the rest of the funds provided through matching by Longecity: for every $1 you donate, $2 will be donated by Longecity.
Do you want to see rapid progress in the foundations of rejuvenation biotechnology? Then do something about it! Putting my money where my mouth is, I donated $1,000 to this project today. I think that it merits your attention as well: look at the research brief, read the SENS Research Foundation's page on mitochondrial repair, and give what you think will help meet the amount. This is the future, in which those of us most interested in any particular research program can collaborate to make it run faster, picking and choosing what we wish to fund first. There will only be more of this going forward, so jump in now, and show your support for rejuvenation research.
INVESTIGATING SIRT3 AS A TARGET FOR CALORIE RESTRICTION MIMETIC DEVELOPMENT
Research into sirtuins emerged from research into the sweeping beneficial metabolic changes that take place due to the practice of calorie restriction. The mainstream research community would like to build drugs, calorie restriction mimetics, that reproduce some fraction of these changes with minimal side-effects. This involves first finding key proteins in the mechanisms that coordinate the metabolic reaction to fewer calories in the diet, and then finding or designing compounds that can change the amounts of those proteins.
So far work on sirtuins has largely meant work on sirtuin 1, and this has generated only knowledge. Despite the hopes for activators of sirtuin 1 (overinflated hopes, as is often the case in areas with significant venture capital invested) this looks like a dead end. There is no reliable extension of life shown in animal studies, and doubts are cast on the early consensus of research in this regard. Nonetheless, there is inertia in funding for this line of research and investigations continue.
Some researchers have moved on to look at mTOR and its activators, as there is far better and more reliable data there for life span extension in mice. Even so, there are good reasons not to buy into another hype machine, one that will no doubt wind up for action the moment that a biotech startup in this area obtains meaningful funding. There is no reason to expect any effort involving metabolic manipulation to slow aging to produce good results for human life extension any time soon. These are enormously challenging, enormously expensive efforts, and the payoff is unlikely to be any greater than that produced by moderate exercise or the practice of calorie restriction. This is peanuts in the grand scheme of things, compared to actual rejuvenation of the old, reversal of aging, that might be obtained through a focus on repairing cellular damage rather than altering metabolism to gently slow the rate at which that damage accrues.
But this is the mainstream of longevity science: a comparatively small research community, of which most are focused on a comparatively poor approach to achieving their end goals. So we come to sirtuin 3, which has been gathering more interest in recent years. This sirtuin, unlike sirtuin 1, is a mitochondrial protein. Mitochondria occupy an important place in the roots of degenerative aging, and levels of sirtuin 3 appear to affect mitochondrial function to a great enough degree to influence health and longevity. As you can see from the title of this open access review paper, there is some enthusiasm for work on sirtuin 3. One might expect that this line of research may too at some point in the near future blossom into an overhyped, venture-funded effort to build a calorie restriction mimetic drug worthy of the name:
Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration
Caloric restriction (CR), fasting, and exercise have long been recognized for their neuroprotective and lifespan-extending properties; however, the underlying mechanisms of these phenomena remain elusive. Such extraordinary benefits might be linked to the activation of sirtuins. In mammals, the sirtuin family has seven members (SIRT1-7), which diverge in tissue distribution, subcellular localization, enzymatic activity, and targets.
SIRT1, SIRT2, and SIRT3 have deacetylase activity. Their dependence on NAD+ directly links their activity to the metabolic status of the cell. High NAD+ levels convey neuroprotective effects, possibly via activation of sirtuin family members. Mitochondrial sirtuin 3 (SIRT3) has received much attention for its role in metabolism and aging. Specific small nucleotide polymorphisms in Sirt3 are linked to increased human lifespan.
SIRT3 mediates the adaptation of increased energy demand during CR, fasting, and exercise to increased production of energy equivalents. SIRT3 deacetylates and activates mitochondrial enzymes involved in fatty acid β-oxidation, amino acid metabolism, the electron transport chain, and antioxidant defenses. As a result, the mitochondrial energy metabolism increases.
In addition, SIRT3 prevents apoptosis by lowering reactive oxygen species and inhibiting components of the mitochondrial permeability transition pore. Mitochondrial deficits associated with aging and neurodegeneration might therefore be slowed or even prevented by SIRT3 activation. In addition, upregulating SIRT3 activity by dietary supplementation of sirtuin activating compounds might promote the beneficial effects of this enzyme.
AN EXTREMELY SUSPICIOUS LOOKING TECHNOLOGY: QUEC PHISIS TM
After reading around longevity science for a few years you start to develop a feel for what sounds suspect: one of the first flags is for something to be so far removed from the spotlight of the mainstream that it would be hard for any mainstream researcher to evaluate it, for example. New technologies have to come from somewhere, however, and they start with small groups of knowledgeable developers and researchers. By their nature these new advances are hard to evaluate at the outset. Mainstream researchers aren't all that interested in spending significant time on serious evaluation given that most radical departures from the norm are in fact wrong directions, or just flat out wrong. Of course sometimes the new and radical departure is the right way forward, an advance that will reshape the whole field for the better - such as the SENS vision for aging. Then progress is as much a matter of slowly gathering support and making your case over a matter of years, bootstrapping a mass of supporting evidence incrementally as you can convince funding sources and researchers that you are right.
This process applies between all groups. I may know enough about the underpinnings of SENS rejuvenation research to judge that it is a good plan, but I'm all at sea when a group starts to talk about modulating cellular activities with low-frequency electromagnetism. So let me say that if QUEC PHISIS TM was not an accepted abstract at SENS6, and not the subject of a paper in the Rejuvenation Research advance publication queue, I would have written this off as exceedingly dubious after the first paragraph. It still looks exceedingly dubious to my eye, based on its similarity to several well-entrenched lines of medical quackery that have been ongoing for decades now. See what you think:
Modulating Biological Events by Biophysics: An innovative Molecular Methodology using Ion Cyclotron Resonance
It has been known since long time that electromagnetic fields characterized by extremely low frequency (ELF) and intensity are able to trigger Molecular Cyclotronic Ion Resonance phenomena. However, only in the last decades, biophysical studies have shown that Molecular Cyclotronic Ion Resonance, thanks to the ELF waves, activates some fundamental elements (proteins, vitamins, mineral salts..) and makes them enter more easily through the cellular membrane thus guiding all the biochemical reactions essential for the normal cellular activity.
The QUEC PHISIS TM QPS1 treatment is programmed to emit specific frequencies of electromagnetic waves tailored to research the most proper approach to restore the cellular metabolism, the optimize the redox balance (rH2) and the acidity (pH) of body fluids. Preliminary clinical data suggest the significant and sudden impact of this device on cardiovascular parameters (flow mediated dilation) in healthy volunteers, a stronger and quicker antioxidant effect than antioxidant drugs, improvement in muscular coordination and performance through better recruitment of neuromotor units in neuromuscular diseases, increase in body (muscular) mass in unhealthy or frail people and enzymatic activation of the basal metabolism and of the fatty acid metabolism has been proved, in aged rats.
Am I qualified to evaluate this in any way? Absolutely not. My decade of reading around longevity science publications doesn't give me much of a footing to say how valid this research is - it is way off in left field in relation to the molecular biology and health studies I normally peruse. I'd have to go and read up on the relevant areas for a few months: it seems that investigation of cyclotronic ion resonance in the context of medical research is an ongoing concern, for example, though sparsely populated. All in all I'd want to see a few other research groups showing the same sorts of results before I'm prepared to treat this as more than a curio.
SCENARIOS FOR THE NEAR FUTURE OF HUMAN LONGEVITY
Governments in much of the world are massive and intrusive. Little of any consequence can be done without considering how government employees will intervene to make matters harder, more costly, or just plain impractical. Therefore there exists an enormous, many-layered industry that works to sway the opinion of politicians and, perhaps more importantly, the many unelected and largely unaccountable career bureaucrats in charge of large budgets or sweeping regulations. In a rational world we'd have none of this, and people would just get on with improving medicine without the need to spend as much money on lobbying as goes to actually building new and better therapies.
It is in this context that I'll point you to an ongoing effort by a lower layer of the lobbying community, one that has some overlap with both the mainstream media and the business of producing data, white papers, and projections on various topics for use by lobbyists. This one concerns the trajectory of the next few decades of human health and longevity, which of course is of great interest to a range of concerns whose agents are pushing for various changes and payouts in the highly regulated healthcare industry. A plague on all their houses from my point of view, as the machinations of politicians and special interests does little but reduce the odds of seeing radical new therapies to extend healthy life. The cost of regulation is very real, and it is measured in lives lost.
So that said, the contents below are of interest as yet another sign that opinions on medicine and longevity are changing. No longer is the status quo of little change in human longevity the only opinion presented by the mainstream. The years of advocacy for longevity science, the scientific results, and the uncertainty over upward bounds on longevity expressed by the actuarial community are starting to be heard. The possibility of radical life extension driven by new directions in medicine, such as the Strategies for Engineered Negligible Senescence and similar repair-based approaches to rejuvenation, is on the table and talked about in public.
Drooling on Your Shoes or Living Long and Prospering?
Humanity's increase in lifespan may be our greatest achievement. Most of the world's children and their parents and grandparents will live long, productive lives. Even counting the wretched of the Earth, the typical person at birth today worldwide can expect to live to nearly 70, up from her 30s in 1900. But what does the future of longevity hold in the United States? Stagnation? Lift-off? The future is impossible to predict. That's why, to think rationally, systematically and long-term about the future, you need scenarios. These are credible stories, faithful to today's facts, that aim to paint dramatically different futures.
Scenario A: Small Change
Small Change is the official Washington future regarding aging - the one many policymakers expect. In Small Change, the exponential increases in the biological, genetic, neurological, information, nano, and implant technologies have relatively minor impact on current trends in lifespan, healthspan, costs, hospitals, health insurance, Social Security, Medicare, Obamacare, and federal policy. It is a straight-line projection from the present - small but persistent incremental medical change, while costs skyrocket.
Scenario B: Drooling on Their Shoes
In Drooling on Their Shoes, the exponential advances in the GRIN technologies (genetics, robotics, information, and nanotechnology) succeed in increasing lifespan, but largely fail at increasing healthspan. In 2030, octogenarians [are] already in assisted living facilities, where they can expect to spend the next 10 or 20 years. Their long lives, such as they are, will be marked by one major medical intervention after another, at tremendous cost - even greater than in Small Change.
Scenario C: Live Long and Prosper
Live Long and Prosper is based on the assumption that the first human to robustly and even youthfully live to the age of 150 is already alive today. Variations on this scenario are the New Conventional Wisdom among some sober scientists. In Live Long and Prosper, we see marked advances in personalized medicine, tissue engineering, organ regeneration, implants, and memory enhancement, as well as novel means of peering into the body and major interventions in heart disease, diabetes, and cancer. Medicine has become an information technology, and thus follows Moore's Law.
Scenario D: Immortality
Immortality is not as crazy a scenario as it sounds. All it requires is for technology to be advancing faster than you're aging. In principle, all you have to do is turn this line into a curve a little - increase this rate by a factor of four - and you have life expectancy advancing one year for every year you age. And you have something that looks like immortality for some people.
The curve actually has to increase somewhat more than a factor of four to reach actuarial escape velocity. Life expectancy at birth gives that multiple, but life expectancy at birth has no relevance to your future life expectancy as an adult at 20, 40, 60, or 80. Life expectancy at older ages is presently creeping forward at about 1 year with every passing decade. But who cares about trends? Trends reflect what is and what was, not what will be. In eras of rapid progress in enabling technologies old trends can break upward to new heights as radical new advances are introduced, changing the whole picture. In this case the radical new advance is to actually treat the root causes of aging, repairing or slowing them, now that the research community can identify both what to do and how to do it. All progress in the upper end of adult life expectancy in the past has been incidental, fortunate accidents and side-effects of better medical technologies whose goals had nothing to do with aging per se. In contrast the sky is the limit when directed and deliberate efforts are made to extend healthy human life and rejuvenate the old.
THE LAST GENERATION TO DIE
The last generation whose members will be forced into death by aging is alive today. It won't be the youngest of us, born in the past few years - they, most likely, have thousands of years ahead of them. It won't be the oldest of us either, as even under the plausible best of circumstances we are twenty to thirty years away from a widespread deployment of rejuvenation therapies based on the SENS research program. As to the rest of us, just who is left holding the short straw at the end of the day depends on the speed of progress in medical science: advocacy, fundraising, and the effectiveness of research and development initiatives. Persuasion and money are far more important at this early stage than worrying about how well the researchers are doing their jobs, however.
We live in a world in which the public is only just starting to come around to the idea that aging can be treated, and demonstrations of rejuvenation in the laboratory could be achieved in a crash program lasting ten to twenty years, at a comparatively small cost. But still, most people don't care about living longer, and most people try not to think about aging, or the future of degeneration and sickness that awaits. They think it is inevitable, but that is no longer true. If you are in early middle age today in the first world, then you have a good shot at living for centuries if the world suddenly wakes up tomorrow and massive funding pours into rejuvenation research. You will age and die on a timescale little different from that of your parents if that awakening persistently fails to happen.
So, roll the dice, or help out and try to swing the odds in your favor. Your choice.
Crowdfunding on Kickstarter and related sites is still the new new thing, the shine not yet worn off. One of the truths that this activity reinforces is that it is far, far easier to raise funding for the next throwaway technological widget than for medical research projects aimed at the betterment of all humanity. Research crowdfunding is a tiny, distant moon orbiting the great mass of comics, games, and devices on Kickstarter, Indiegogo, and others. Hell, it's easier to crowdfund a short film that points out how close human rejuvenation might be to the present day than it is to crowdfund a project to actually conduct a portion of that research. Is this a reflection of rationality? You decide, though it could be argued either way regarding whether a dollar given to raising awareness is more valuable than a dollar given to the researchers at this point in time. Both research and persuasion need to happen.
The Last Generation To Die - A Short Film
Set in the future when science first begins to stop aging, a daughter tries to save her father from natural death. The story takes place roughly 30 years in the future at the moment when science has first figured out how to stop aging through genetics. It is framed around the gulf between generations that would occur with the first release of this technology. A daughter who works for a company called Aperion Life - the first to bring this new technology to the public - wants to save her aging father. She starts him on the trials but he soon stops coming. The film continues with the conflict rising between them as she wants him to live on with her while he feels a natural ending is more human.
The film centers itself around the natural conflict that would exist at this divide. Upon developing this story, I've asked many people and I've found a pretty even 50/50 divide of opinions strongly on one side or the other- either they want to die naturally and believe there is beauty in finality, or they want to see what the future holds and have more time to explore and learn more in life. I'd like to turn the question to you... Which side are you on? Would you want to live on or die naturally?
I feel this is a film that needs to be made. Asking these questions in the form of art and story will help start the discussion. Our world is changing very fast and the rate of technology is speeding up. What does all of this mean for humanity? Everything we know, from a book to a play to a song, ends... What does it mean when there is no ending? Would we be more complacent? Would life be as meaningful? Is there more of a beauty in the way it has always been with our passing or is there more beauty in our bodies and minds staying fresh and alive for many, many years to come? What about social justice and overpopulation? Would life become boring after living on indefinitely or would you find it exhilarating to have time to learn new languages, instruments, subjects - to read more books, to love more - to live several lifetimes? Would it be worth it if some of your most loved friends or relatives passed on and wouldn't live on with you? Are you interested in seeing what the future brings in technology and social evolution or are you happy to have contributed and be a part of it for a short time?
Tim Maupin's Film, 'The Last Generation to Die', to Explore Longevity and Life Extension
Chicago filmmaker Tim Maupin launched a Kickstarter for a short film titled, "The Last Generation to Die." Maupin thinks now is a great time to start a conversation about life extension. And he's right. The idea that within decades a genetic fountain of youth may plausibly reverse the aging process, even indefinitely stave off death, seems to be rising up in pop culture. Maupin's Kickstarter has so far raised over $15,000 - $6,000 more than its initial funding goal. Encouraged by the positive response, they're dreaming bigger and hope to fund a stretch goal of $25,000 in the last 10 days of the campaign.
LATEST HEADLINES FROM FIGHT AGING!
FGT-1 KNOCKDOWN EXTENDS LIFE IN NEMATODE WORMS
Monday, September 23, 2013
Here is one example of ongoing explorations of the intersection between metabolism and longevity in lower animals. It is an open access paper, so you might take a look at the full PDF version:
Caenorhabditis elegans is widely used as a model for investigation of the relationships between aging, nutrient restriction and signalling via the DAF-2 receptor for insulin-like peptides and AGE-1 (PI 3-kinase) but the identity of the glucose transporters (GLUTs) that may link these processes is unknown. We unexpectedly find that of the eight putative GLUT-like genes only the two splice variants of one gene have a glucose transport function in an oocyte expression system. We have named this gene (fgt-1 (Facilitated Glucose Transporter, isoform 1).
We show that knockdown of fgt-1 RNA leads to loss of glucose transport and reduced glucose metabolism in wild type worms. The FGT-1 glucose transporters of C. elegans thus play a key role in glucose energy supply to C. elegans. Importantly, knockdown of fgt-1 leads to an extension of lifespan equivalent, but not additive, to that observed in daf-2 and age-1 mutant worms. Our data are consistent with DAF-2 and AGE-1 signalling to glucose transport in C. elegans and this process being associated with the longevity phenotype in daf-2 and age-1 mutant worms. We propose that fgt-1 constitutes a common axis for the life-span extending effects of nutrient restriction and reduced insulin-like peptide signalling.
TOWARDS A STEM CELL THERAPY FOR PERIODONTITIS
Monday, September 23, 2013
Dentistry will benefit from stem cell technologies just like the rest of medicine. While the public eye is generally focused on the tissue engineering of new teeth, the ability to regenerate gums and other supporting structures that surround the teeth is just as important.
Mesenchymal stem cells (MSC) have been considered as a potential therapy for the treatment of periodontal defects arising from periodontitis. However, issues surrounding their accessibility and proliferation in culture significantly limit their ability to be used as a mainstream treatment approach. It is therefore important that alternative, easily accessible, and safe populations of stem cells be identified.
Controlled induction of induced pluripotent stem cells (iPSC) into MSC-like cells is emerging as an attractive source for obtaining large populations of stem cells for regenerative medicine. We have successfully induced iPSC to differentiate into MSC-like cells. The MSC-like cells generated satisfied the International Society of Cellular Therapy's minimal criteria for defining multipotent MSC, since they had plastic adherent properties, expressed key MSC-associated markers, and had the capacity to undergo tri-lineage differentiation. Importantly, the resulting iPSC-MSC-like cells also had the capacity, when implanted into periodontal defects, to significantly increase the amount of regeneration and newly formed mineralized tissue present.
Our results demonstrate, for the first time, that MSC derived from iPSC have the capacity to aid periodontal regeneration and are a promising source of readily accessible stem cells for use in the clinical treatment of periodontitis.
A STUDY OF METABOLISM AND LIFELONG CALORIE RESTRICTION IN DOGS
Tuesday, September 24, 2013
The practice of calorie restriction, eating fewer calories while still maintaining an optimal intake of nutrients, produces sweeping beneficial changes in metabolism. It produces larger short term changes in measures of health in humans than any presently available medical technology, and can extend maximum life span in laboratory animals such as mice by up to 40%. In longer lived species it seems that any extension of life becomes shorter, however, even while the short term changes in metabolism, health measures, and metabolic processes remain very similar - which is a puzzle.
Modeling aging and age-related pathologies presents a substantial analytical challenge given the complexity of gene-environment influences and interactions operating on an individual. A top-down systems approach is used to model the effects of lifelong caloric restriction, which is known to extend life span in several animal models. The metabolic phenotypes of caloric-restricted (CR; n = 24) and pair-housed control-fed (CF; n = 24) Labrador Retriever dogs were investigated [to] model both generic and age-specific responses to caloric restriction.
Three aging metabolic phenotypes were resolved: (i) an aging metabolic phenotype independent of diet, characterized by high levels of glutamine, creatinine, methylamine, dimethylamine, trimethylamine N-oxide, and glycerophosphocholine and decreasing levels of glycine, aspartate, creatine and citrate indicative of metabolic changes associated largely with muscle mass; (ii) an aging metabolic phenotype specific to CR dogs that consisted of relatively lower levels of glucose, acetate, choline, and tyrosine and relatively higher serum levels of phosphocholine with increased age in the CR population; (iii) an aging metabolic phenotype specific to CF dogs including lower levels of lipoprotein fatty acyl groups and allantoin and relatively higher levels of formate with increased age in the CF population.
There was no diet metabotype that consistently differentiated the CF and CR dogs irrespective of age. Glucose consistently discriminated between feeding regimes in dogs (≥312 weeks), being relatively lower in the CR group. However, it was observed that creatine and amino acids (valine, leucine, isoleucine, lysine, and phenylalanine) were lower in the CR dogs (earlier than 312 weeks), suggestive of differences in energy source utilization. [Analysis] of longitudinal serum profiles enabled an unbiased evaluation of the metabolic markers modulated by a lifetime of caloric restriction and showed differences in the metabolic phenotype of aging due to caloric restriction, which contributes to longevity studies in caloric-restricted animals.
TFAM, AGING, AND CALORIE RESTRICTION
Tuesday, September 24, 2013
In recent years, researchers have shown that introducing additional mitochondrial transcription factor A (TFAM) can reverse some age-related loss of mitochondrial function. Research on mitochondrial protofection seems to have been sidetracked by this finding also - the researchers were using TFAM as a part of a means to replace damaged mitochondrial DNA, but are now more focused on TFAM itself, arguably a less useful path forward.
In this research, scientists show that TFAM levels differ in old and young rats, and life-long calorie restriction eliminates that difference. Calorie restriction slows aging and improves near every measure of metabolism examined to date, so we should expect to see it reduce any given difference between old and young tissues. As for many lines of research, this points to the importance of mitochondria in aging:
Aging affects mitochondria in a tissue-specific manner. Calorie restriction (CR) is, so far, the only intervention able to delay or prevent the onset of several age-related changes also in mitochondria. Using livers from middle age (18-month-old), 28-month-old and 32-month-old ad libitum-fed and 28-month-old calorie-restricted rats we found an age-related decrease in mitochondrial DNA (mtDNA) content and mitochondrial transcription factor A (TFAM) amount, fully prevented by CR. We revealed also an age-related decrease, completely prevented by CR, for the proteins PGC-1α, NRF-1 and cytochrome c oxidase subunit IV, supporting the efficiency of CR to forestall the age-related decrease in mitochondrial biogenesis. Furthermore, CR counteracted the age-related increase in oxidative damage to proteins, represented by the increased amount of oxidized peroxiredoxins in the ad libitum-fed animals.
To investigate further the age- and CR-related effects on mitochondrial biogenesis we analyzed the in vivo binding of TFAM to specific mtDNA regions and demonstrated a marked increase in the TFAM-bound amounts of mtDNA at both origins of replication with aging, fully prevented by CR. A novel, positive correlation between the paired amounts of TFAM-bound mtDNA at these sub-regions was found in the joined middle age ad libitum-fed and 28-month-old calorie-restricted groups, but not in the 28-month-old ad libitum-fed counterpart suggesting a quite different modulation of TFAM binding at both origins of replication in aging and CR.
Considering all together the present results, we demonstrate in rat liver a very articulated age-related decrease in mitochondrial biogenesis leading to the loss of mtDNA probably also through the increase of TFAM binding to both origins of replication. [This] gives an interesting and novel clue to evaluate the preservation of mitochondrial biogenesis as very relevant in the anti-aging action of CR. Of course, future work will be necessary to further verify such hypothesis also in consideration of the therapeutic applications that might lead, through up-regulation of PGC-1α expression and maintenance of mtDNA, to a longer-lasting mitochondrial functionality.
A DEMONSTRATION OF REDUCED AGE-RELATED HEARING LOSS IN MICE
Wednesday, September 25, 2013
Researchers have been investigating ways to restore sensory hair cells in the ear for some years now. These cells are lost with age, leading to a form of age-related hearing loss. Here researchers reduce this loss through raising levels of the protein islet1:
Isl1 is a LIM-homeodomain transcription factor that is critical in the development and differentiation of multiple tissues. In the mouse inner ear, Isl1 is expressed in the prosensory region of otocyst, in young hair cells and supporting cells, and is no longer expressed in postnatal auditory hair cells. To evaluate how continuous Isl1 expression in postnatal hair cells affects hair cell development and cochlear function, we created a transgenic mouse model in which the Pou4f3 promoter drives Isl1 overexpression specifically in hair cells.
Isl1 overexpressing hair cells develop normally, as seen by morphology and cochlear functions (auditory brainstem response and otoacoustic emissions). As the mice aged to 17 months, wild-type (WT) controls showed the progressive threshold elevation and outer hair cell loss characteristic [of] age-related hearing loss (ARHL). In contrast, the Isl1 transgenic mice showed significantly less threshold elevation with survival of hair cells. Further, the Isl1 overexpression protected the ear from noise-induced hearing loss (NIHL): both ABR threshold shifts and hair cell death were significantly reduced when compared with WT littermates.
Our model suggests a common mechanism underlying ARHL and NIHL, and provides evidence that hair cell-specific Isl1 expression can promote hair cell survival and therefore minimize the hearing impairment that normally occurs with aging and/or acoustic overexposure.
A MEASURE OF THE DEGREE TO WHICH TELOMERE LENGTH IS INHERITED
Wednesday, September 25, 2013
Telomeres are caps at the ends of chromosomes, and their average length, while dynamic, tends to become shorter with advancing age or illness. To my eyes this looks like a secondary effect of the damage of aging, but there are researchers who think that it might be a primary cause of degenerative aging and are working on ways to lengthen telomeres, such as through the use of the enzyme telomerase.
Natural variations in life span in humans are to some degree inherited, depending upon both genes and lifestyle choices. Here is a study that puts some numbers to telomere length inheritance:
Telomeres play a central role in cellular senescence and are associated with a variety of age-related disorders such as dementia, Alzheimer's disease and atherosclerosis. Telomere length varies greatly among individuals of the same age, and is heritable. Here we performed a genome-wide linkage scan to identify quantitative trait loci (QTL) influencing leukocyte telomere length (LTL) measured by quantitative PCR in 3,665 American Indians (aged 14 - 93 years) from 94 large, multi-generational families. All participants were recruited by the Strong Heart Family Study (SHFS), a prospective study to identify genetic factors for cardiovascular disease and its risk factors in American Indians residing in Oklahoma, Arizona and Dakota.
LTL heritability was estimated to be between 51% and 62%, suggesting a strong genetic predisposition to interindividual variation of LTL in this population. The strongest evidence of linkage for LTL in our genome-wide scan was localized to chromosome 13q12 in the Oklahoma population. [Among nearby genes, two] could represent promising candidate genes for LTL in American Indians. One is the well-known aging gene Klotho (KL) and [another] is poly (ADP-ribose) polymerase family, member 4 (PARP4). The PARP enzymes recognize DNA strand damages, and DNA binding by PARP controls telomere length and chromosomal stability by triggering its own release from DNA ends. Apart from KL and PARP4, the 13q linkage peak also includes known candidate genes for inflammation, e.g., arachidonate 5-lipoxygenase-activating protein (ALOX5AP), and cancer, e.g., breast cancer 2 early onset (BRCA2), all of which may be involved in the aging process.
THE PROSPECTS FOR THERAPIES BASED ON HETEROCHRONIC PLASMA EXCHANGE
Thursday, September 26, 2013
Heterochronic parabiosis is the process of linking together the circulatory systems of an old and a young individual. This is done in mice to try to isolate the roles of various signaling proteins in age-related alterations to metabolism, stem cell activity, and so forth. The older mice tend to show improvements in various short-term measures that otherwise decline with age.
While the full details of what is going on under the hood are not yet understood, why not trial a human therapy based on regular blood transplants from a young donor to an old recipient? This would be a stopgap on the way to figuring out the laundry list of signals that need to be altered and then altering them directly - which is in turn a stopgap on the way to repairing the underlying damage of aging that causes these signaling and metabolic changes, as well as many other forms of harm.
My guess is that in the present regulatory environment such a therapy would be unlikely to emerge. There is a very strong bias against progressing without a full explanation of the underlying molecular biology these days - therapies of the past are grandfathered in, but would never be admitted to clinical trials in today's risk averse world. As and when a comprehensive explanation emerges, researchers will focus on direct manipulation of the signals in question rather than developing a blood transfusion methodology to carry them over.
The population of baby boomers (age 60-65) is rapidly increasing globally. The aging of the human body is associated with the decline of cellular function which leads to the development of a variety of diseases. The increased demand for health care for the aging population creates significant financial burden to any healthcare system. Developing strategies and health intervention methods to ameliorate this situation is paramount.
Experiments utilizing heterochronic parabiosis in mice have demonstrated that replacing the aging cellular milieu with the plasma of a young experimental animal leads to reversal of cellular senescence. This article describes a hypothetical model of intermittent heterochronic plasma exchange in humans as a modality for heterochronic parabiosis in an attempt to delay cellular senescence.
AUTOANTIBODY MECHANISMS AS A BASIS FOR THERAPIES TO CLEAR SENESCENT CELLS
Thursday, September 26, 2013
Senescent cells are those that have existed the cell cycle of continual division, due to either age or damage. They should destroy themselves or be destroyed by the immune system, but not all are, and that number increases greatly in older age, not least because the immune system declines and fails due to aging. Senescent cells that are not destroyed emit harmful signals to surrounding tissue, degrading function and encouraging more of their neighbors to also become senescent.
This paper looks at a mechanism by which the immune system clears out senescent cells. It is entirely plausible that these activities can be enhanced via suitable therapies, helping to greatly cut down the number of senescent cells hanging around to contribute to degenerative aging. Note that the paper is open access, but the full version available for download is PDF only.
Physiologic autoantibodies, that is, those with an active physiologic role, are an important part of the normal human immune system and are essential in maintaining homeostasis. Evidence suggests that the body uses autoantibodies to prevent disease and to self-treat diseases once started. This suggests a potential therapeutic role for autoantibodies, or, even better, a way to use them to prevent disease. Their capacity to remove aged, damaged cells is well established. Immunoglobulin (Ig) G autoantibodies bind to senescent cell antigen (SCA), which is an altered band 3 anion exchanger protein found mainly on aged cells. Once bound, IgG triggers the removal of the senescent cells by macrophages.
Band 3 is altered primarily by oxidation, which in turn generates SCA. These studies demonstrated that oxidation can generate neoantigens that the immune system will recognize. Band 3 isoforms are ubiquitous: they have been found in all mammalian cells and species so far examined.
The innate immune response to band 3 membrane proteins, and their regulation of cellular lifespan and therapeutic potential will be presented. Examples of other potential innate and physiologic autoantibodies include neuroprotective antibodies to amyloidgenic toxic peptides and antibodies to oxidized LDL (OxLDL), which modify the natural progression of atherosclerosis.
CELLULAR SENESCENCE AND ITS RELATIONSHIP WITH CANCER
Friday, September 27, 2013
Cells that are old or damaged become senescent and change their behavior for the worse, emitting signals that harm surrounding tissue and increase the chance of other nearby cells becoming senescent. These cells should destroy themselves or be destroyed by the immune system, but some survive, and their growing presence is one of the root causes of degenerative aging. As this short primer notes, we might consider cellular senescence to be an evolving battlefield, a portion of the fight with cancer: cellular senescence is an anti-cancer mechanism that is partially subverted by cancer.
Senescence has been shown to prevent and promote tumorigenesis. These results are not so paradoxical. To develop and maintain, organisms rely on cellular growth and cell division. As organisms age, deregulations of these processes appear leading to hyperplastic or degenerating diseases, such as cancer and Alzheimer disease, respectively. Interestingly, these two aged-related diseases have been linked to a cellular response that yet, uncouples cellular growth from cell division: senescence.
Senescence is a natural cellular response that can be triggered by various stimuli, such as telomere shortening, oncogenic stresses or unrepaired DNA damages. Senescent cells grow but do not divide so that they are enlarged and restricted in number. In addition, as they do not proliferate due to the irreversible cell cycle arrest, they do not differentiate. Thus senescence modifies tissue homeostasis by profoundly impacting tissue architecture both physically and biologically. Such disorganisation leads to alteration of cell contacts thereby re-wiring cellular communication.
To communicate, cells use physical interactions and diffusible factors. In that context, it is interesting to observe that senescent cells often release factors such as cytokines or growth factors. This is known as senescence associated secretory phenotype (SASP). It is therefore tempting to suggest that one of the outcomes of senescence is tissue re-organisation, achieved via cell communication, to reach new homeostasis upon cellular stress. As a matter of fact, studies of senescent cancer cells suggest so. First, senescence has been shown to act as an anti-cancer barrier, both physically and biologically in preneoplastic tissue. Secondly, it has been shown to promote tumorigenesis by favoring the emergence of cancer stem-like cells (CSLCs).
CSLCs are rare quiescent cells. They niche in heterogeneous tumors and have, in contrast to the bulk tumor cells but similarly to normal stem cells, the ability to self renew and to differentiate. Thus, if tissue has to be re-organised upon senescence to gain minimal homeostasis for functioning, new cells have to emerge and differentiate. This can be achieved by stimulation of CSLCs by SASP factors released from senescent cancer cells.
Of note, it remains unclear why CSLCs, unlike normal stem cells, do not senesce. In relation to their role in tissue architecture, it has been described that CSLCs preferentially develop, within the tissue mass, under hypoxic conditions. Interestingly, hypoxia has been shown to inhibit mTOR, which converts quiescent cells into senescent cells. If experimentally verified, hypoxia could reinforce the intrinsic resistance of CSLCs by maintaining their quiescent state, while inhibiting mTOR and geroconversion of CSLCs from quiescence to senescence.
It therefore appears, at least in pathological cancer tissue, that senescence, and SASP in particular, could play a pivotal role in tissue re-organisation upon cellular stress. As a consequence, depending on the cancer stage, i.e. to which extent tissue has to be re-organised upon cancer invasion, senescence could be pro or anti tumorigenic.
EXPLORING THE ROLE OF NATURAL ANTIOXIDANTS INSIDE MITOCHONDRIA
Friday, September 27, 2013
Mitochondria are evolved remnants of symbiotic bacteria within our cells. They produce chemical energy stores used to power cellular operations, but that process also produces damaging oxidative molecules, and the mitochondria themselves bear the brunt of that. Unfortunately some rare forms of the resulting damage sabotage mitochondrial machinery in ways that propagate throughout a cell's herd of mitochondria, turning the entire cell into a malfunctioning exporter of harmful oxidative molecules. The growing numbers of such cells in the body cause increasing harm, and this is one of the contributing causes of degenerative aging.
There are natural antioxidants present in mitochondria, such as forms of superoxide dismutase, and the situation would - in theory - be far worse without them. Researchers have shown that boosting the levels of some of these antioxidants can be beneficial in mice, and targeting designed antioxidant molecules to the mitochondria can similarly produce benefits to health and life span.
Interestingly it is possible to extend life in some cases by reducing the level of natural antioxidants in the mitochondria. In this case it is thought that increased levels of oxidants produce a hormetic response in cells, driving more housekeeping and maintenance activities to create a net benefit. The inner workings of mitochondria are both very complex and very important to metabolism and aging, and the results of any change to these mechanisms can be counterintuitive:
The processes that control aging remain poorly understood. We have exploited mutants in the nematode, Caenorhabditis elegans, that compromise mitochondrial function and scavenging of reactive oxygen species (ROS) to understand their relation to lifespan.
We discovered unanticipated roles and interactions of the mitochondrial superoxide dismutases (mtSODs): SOD-2 and SOD-3. Both SODs localize to mitochondrial supercomplex I:III:IV. Loss of SOD-2 specifically (i) decreases the activities of complexes I and II, complexes III and IV remain normal; (ii) increases the lifespan of animals with a complex I defect, but not the lifespan of animals with a complex II defect, and kills an animal with a complex III defect; (iii) induces a presumed pro-inflammatory response. Knockdown of a molecule that may be a pro-inflammatory mediator very markedly extends lifespan and health of certain mitochondrial mutants.
The relationship between the electron transport chain, ROS, and lifespan is complex, and defects in mitochondrial function have specific interactions with ROS scavenging mechanisms. We conclude that mtSODs are embedded within the supercomplex I:III:IV and stabilize or locally protect it from reactive oxygen species (ROS) damage.