FIGHT AGING! NEWSLETTER
May 6th 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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- SENS Research Foundation Annual Report for 2012
- A Different Take on NF-κB and the Hypothalamus
- Adjusting Mouse Longevity via the Hypothalamus
- Video: Aubrey de Grey at TEDxDanubia 2013
- Latest Headlines from Fight Aging!
- T-Regulatory Cells More Numerous in the Aged Immune System
- HMGA1 as a Potential Common Mechanism in Cancer
- A Skeptical View of Mitochondrial DNA Damage and Aging
- Protecting Cryonics Patients
- A Review of Adenylyl Cyclase Type 5 and Longevity in Mice
- On Extending Mouse Longevity
- Growth Hormone and IGF-1 in Aging
- IGF1R Levels in the Brain Correlate With Species Life Span
- Calorie Restriction and Calorie Restriction Mimetics
- The Burrill and Buck Aging Meeting, May 20th 2013
SENS RESEARCH FOUNDATION ANNUAL REPORT FOR 2012
The SENS Research Foundation is one of the few organizations presently focused on developing medical technologies that will produce rejuvenation in the old. The Foundation researchers and staff undertake targeted research programs in areas that are not getting enough attention from the mainstream life science community, and engage in advocacy to convince more of the research community to work on the goal of reversing degenerative aging, thus preventing age-related disease, frailty, and disability, and extending healthy life.
A newsletter from the Foundation arrived today, with a link to the Foundation's 2012 annual report (PDF). Good news on the budgetary side of things is the order of the day, and the Foundation is continuing to grow its research efforts. The total budget in 2012 was $3 million, in comparison to the $1 million only a couple of years earlier:
We are pleased to report that, in 2012, SENS Research Foundation was able to support expenses that were double those from the previous year. This was made possible through not only the continued support of our generous donors, but the first in a series of annual disbursements from the de Grey family trust, which together caused SRF's income to increase by about $2 million.
As a research-based outreach organization, the scientific work that we fund plays a critical role in our mission. For this reason, we have focused our growth on our extramural research program, tripling its size by adding more than $750,000 of funding. This aggressive expansion has led to the addition of nine new projects, including two at the Wake Forest Institute for Regenerative Medicine, bringing our total funded to seventeen. Meanwhile, we were able to add $300,000 to our intramural research budget, bringing a third major project, more staff, and new equipment to our Research Center in Mountain View, California.
Simultaneously, we built SRF Education into a larger and more robust educational program, creating our first online course and a successful summer internship program that involved both our Research Center and the Buck Institute for Research on Aging. This has set the stage for further growth in 2013, which will include the development of more coursework and the addition of new internship campuses.
Overall, our expenses in 2013 should increase by an amount equal to 2012's increase. Given our secure base of funding sources, we expect to sustain this higher level of operation indefinitely. We are deeply appreciative of the individuals and foundations that enable us to pursue our mission through their support. We would like to thank Peter Thiel, Jason Hope, the de Grey family trust, the Methuselah Foundation, and the many other donors who make all of our efforts possible.
If you read through the report, you'll find good overviews of the present research programs supported by the Foundation, as well as news of recent progress.
Researchers funded by the Foundation are searching for bacterial enzymes that can be safely introduced into the body to break down harmful metabolic byproducts that build up in the lysosomes within cells, degrading their ability to keep up with cellular housekeeping, and contributing to a range of age-related conditions. There are many different types of chemical gunk that building up in the lysosome, so researchers have so far focused on those best known to the research community.
At the SENS Research Foundation Research Center (SRFRC), our Lysosomal Aggregates team is working to efficiently deliver promising A2E-degrading enzymes identified in our earlier research into the lysosome of cells. One in particular (SENS20) has demonstrated tremendous efficacy in degrading A2E not only in vitro but in A2E-loaded retinal pigment epithelium cells.
In 2013, the team will put a recombinant form of SENS20 to the test, assessing its ability to degrade A2E in vitro and in retinal pigment epithelium cells, and verifying that it is not toxic to the cell
It has to be said that it is very pleasing to see the Foundation at the stage of giving the characteristic drug/therapy candidate names (SENS20 in this case) to the results of their work.
Our mitochondria become damaged with age, causing a range of catastrophic consequences to our cells and tissues. The SENS approach to fixing this is to put backup copies of vulnerable mitochondrial genetic material into the cell nucleus. The challenge here was never getting the genes into the nucleus, as that's just straightforward gene therapy, but rather getting the proteins from those genetic blueprints back into the mitochondria where they are needed. This was slow going until fairly recently, when a potential game-changing advance emerged from the broader research community.
It sounds like the SENS Research Foundation folk are working to integrate this new approach into their efforts, as it could in theory allow all the necessary genes to be moved into the nucleus via the same basic method - so get it working once and you're done.
SRF-RC scientists are now working to master and refine a superior method for accomplishing this goal. Our team has taken four cell lines from patients suffering from severe diseases caused by inherited mitochondrial mutations, and made stable lines that express their improved mitochondrial gene constructs. They have begun collecting data confirming the targeting of gene transcripts and proteins to their mitochondrial locations, and the functional activity of the mitochondrial energy system, in such re-engineered cells.
I am very impatient to see a demonstration of mitochondrial repair or DNA replacement running in a mouse life span trial - it is my belief, based on the range of research I've seen over the years, that mitochondrial damage is the dominant cause of degenerative aging, and I'm looking forward to seeing just how right or wrong that hypothesis might be. It's not unrealistic at this point to think that ten years from now we'll have that data in hand.
Extracellular Matrix Stiffening
Crosslinks such as advanced glycation end-products form relentlessly in our tissues, gumming up protein machinery and causing a fair portion of the visible symptoms of skin aging - and worse, the loss of flexibility in blood vessels and other important tissue structures. Old skin I could live with, but you can't live with old blood vessels; they'll kill you in the course of time. The short history of attempts to develop therapies to break down AGEs has been a short history of frustration, with only very limited success to date. Fortunately, we are now past a critical point of discovery regarding AGEs, which is that in human tissue they overwhelmingly consist of a single compound called glucosepane. Unfortunately, beyond the SENS Research Foundation next to nobody cares to do anything about this aspect of aging.
Late in 2012, we announced the establishment of our new SENS Research Foundation Laboratory in partnership with the University of Cambridge Institute of Biotechnology. In collaboration with Dr. Spiegel's lab, the SRF Cambridge center will initiate work on new agents to cleave apart crosslinked proteins, restoring youthful elasticity and buffering capacity to arteries. The specific molecular target will be glucosepane, the main crosslink that accumulates in aging human arteries and other tissues.
Dr. Spiegel has already developed a way to synthesize glucosepane in the lab; this artificially-produced glucosepane can now be used to develop reagents that can rapidly and specifically detect proteins that have been crosslinked by it.
The Cambridge group has been working on methods of extracting crosslinked proteins intact from the tissues of dogs and marmoset monkeys, and to measure glucosepane cleavage in the test tube and in animal and human tissues. It is clear from this research that none of the commercially available monoclonal antibodies against related crosslink molecules are able to cleave glucosepane to any significant degree, and many are useless. All of these findings further emphasize the importance of this project in developing novel crosslink-breaking therapies.
Other Research Programs
A range of other current research programs are given just as much attention in the annual report. I hope that the notes above encourage you to look them over. This is what the future of longevity science looks like: deliberately and carefully working to reverse specific forms of damage that occur in old tissue but not in young tissue. It is a world away from the old school drug discovery process in the Big Pharma mainstream that aims only at modestly slowing down aging - the sirtuins, and resveratrol, and rapamycin, and all the other potential and so far largely disappointing age-retarding drugs. SENS is the only path forward that is likely to produce significant rejuvenation in the old when its therapies are ready for clinical use.
For you and I to have a good shot at living far longer than our ancestors, the SENS approach must come to dominate the mainstream of aging research, displacing less effective and more expensive approaches. Fast progress requires large budgets and hundreds of researchers. The sooner that this happens, the more likely it is that we will still be alive and in good health when rejuvenation therapies arrive.
ADJUSTING MOUSE LONGEVITY VIA THE HYPOTHALAMUS
NF-κB shows up in a number of places in longevity research, and it's associated with mechanisms known to mediate the relationship between metabolism and the pace of aging. In particular it is associated with the processes of inflammation, which regular readers will know are significant in the aging process. The immune system falls into a malfunctioning state of worsening chronic inflammation in later life, and this contributes to further degenerative aging to some degree.
Selective inhibition of NF-κB has been shown to extend life span in flies, as well as revert some aspects of skin and blood vessel aging in mice. This might have something to do with diminished inflammation, or it may work through other mechanisms, such as alterations to insulin signaling - which is a whole other collection of genes and biochemistry that often appears in aging research.
Nothing happens in isolation in biology. Many of these longevity-associated genes are involved in low-level processes like transcription that influence all of our biochemistry in some way or another, or take part in so many different mechanisms that it's hard to pin down their effects to some simple, clear, single outcome.
In any case, my attention was directed today to a new study in which researchers manipulate NF-κB in the brain to modestly extend life in mice. Interestingly, this also adds to the short list of interventions that can be used to move life span in either direction. Less NF-κB activity means a longer life, and more of it shortens life. In addition, the authors claim that NF-κB inhibition has a positive influence on neurogenesis in the brain, not just on the state of the immune system. The paper isn't open access, unfortunately, so you might start with this article from the science press by way of an overview:
The researchers said they have speeded up and slowed down the rate of ageing in laboratory mice by manipulating chemical messengers that affect the hypothalamus, which is known to play a fundamental role in growth, development, reproduction and metabolism. The [study] focused on a molecule known to be central to the many biochemical reactions involved in the process of inflammation, which is important in many age-related conditions. "As people age, you can detect inflammatory changes in various tissues. Inflammation is also involved in various age-related diseases, such as metabolic syndrome, cardiovascular disease, neurological disease and many types of cancer."
By manipulating the levels of the molecule, known as NF-κB, within the hypothalamus, the researchers were able to slow down the rate of ageing and increase longevity of mice by up to 20 per cent. The team also found that they could slow the rate of cognitive decline by up to 50 per cent, which they could measure by how easy the mice remember how to find their way out of a maze.
A DIFFERENT TAKE ON NF-κB AND THE HYPOTHALAMUS
As reported a couple of days ago, researchers have again demonstrated a link between aging and NF-κB, altering its levels in the hypothalamus it to both modestly lengthen and shorten life in mice. This may be completely a matter of dialing down chronic inflammation in later life, or it may also touch on other common ground in the overlap between metabolism and aging such as insulin signaling.
In the course of their work, the researchers followed some of the connections in this biological jigsaw puzzle to study other proteins and genes involved in generating extended life in mice via inhibition of NF-κB in the hypothalamus. One of these is gonadotropin-releasing hormone (GnRH), and the researchers found that enhancing its levels in the hypothalamus has much the same effect as inhibition of NF-κB. This side of the research gained the attention of the fellow who runs Extreme Longevity:
[The scientists] showed that regular GnRH administration to middle aged mice increased the number of brain cells and reduced signs of aging in the animals. To wit they specially said "GnRH treatment (peripheral) reduced the magnitude of ageing histology in control mice," and "GnRH led to an amelioration of ageing-related cognitive decline."
But of course the holy grail question here is simply can regular peripheral administration of GnRH increase lifespan? I contacted lead author Dongshen Cai MD-PhD and asked if the group had any lifespan data on regular GnRH treatment.
"We don't have lifespan data regarding GnRH treatment," he replied.
Too bad. Imagine if simply a weekly or so injection of GnRH from early middle age onwards could lead to decades more good health and reduction of disease? [Clearly] this is an experiment that should be tried in animals right away. Fortunately Dr. Cai agrees, "it is in our plan," he says.
It has to be said that I generally don't think of this sort of study in these terms. I'm not looking to see whether there's a treatment that can be pulled out, because in most cases a 20% life extension in mice by some form of metabolic manipulation (gene therapy, altering levels of proteins, and so forth) isn't going to be all that relevant to the future of human longevity. For one, it's not rejuvenation, it's only slowing aging. Secondly, mice have very plastic life spans, as is the case for most shorter-lived species. All sorts of things that are either known to do very little to nothing for human life span or are expected to do very little to nothing for human life span can nonetheless extend life by 10%-30% in mice.
So what I see here in the NF-κB / GnRH work is the potential for a therapy that might be applied to modestly reduce inflammation or improve the metabolic profile of older people. Something comparable to rapamycin, in other words, a marginal gain. Perhaps it's a little better than today's best therapies that produce similar effects, and perhaps it's not. I'll wager that it's not going to be as good as regular exercise and calorie restriction. So overall it's not something that I'd give a lot of time and interest to. As a general rule if a research result isn't producing actual rejuvenation then it's not going to have the potential to be a part of greatly extending lives in humans. We have a medical industry presently near-entirely focused on picking mechanisms like this and then using them to produce palliative, marginally effective patches to slap over some of the end stage consequences of aging. The dominant paradigm is to try to alter metabolism late in the game for a small benefit, and without attempting repairing the underlying damage that caused all the harm in the first place. This is a paradigm doomed to poor results, high costs, and ultimate failure.
We have to move on past this methodology of medicine and clinical application of research. The future is SENS and similar projects that aim to repair the causes of aging rather than putting patches on the consequences. It seems fairly clear to me from the performance of the medical establishment to date that only repair can be reliably expected to grant us additional decades of healthy life.
VIDEO: AUBREY DE GREY AT TEDXDANUBIA 2013
Aubrey de Grey is a tireless advocate for the development of rejuvenation biotechnology, the means to repair and reverse the root causes of aging, and he is the more visible face of the SENS Research Foundation - which is not to diminish the hard work of the many other folk, staff and volunteers, who have helped to make the Foundation the growing success it is today. Without their efforts the path towards human rejuvenation would be far longer. If you've been following along these past years, you'll know that de Grey travels widely to give a great many presentations to the public, and here is one example from a recent TEDx event in Hungary.
The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!
LATEST HEADLINES FROM FIGHT AGING!
T-REGULATORY CELLS MORE NUMEROUS IN THE AGED IMMUNE SYSTEM
Friday, May 3, 2013
The immune system malfunctions with age, producing harmful chronic inflammation while failing to adequately respond to pathogens and failing to destroy potentially cancerous and senescent cells. Characteristic changes in immune cell populations accompany these changes, and in past years researchers have shown that adjusting these populations by destroying some of the unwanted immune cells can reverse at least some immune system declines.
Here is an open access paper that focuses on changes in the population of regulatory T cells with aging. These are cells involved in suppressing the immune response, for example so as to prevent the immune system from attacking healthy tissues:
Over the course of the human life, age-related diseases develop because of the failure of genetic traits to remain beneficial, as they were in younger years when they aided in successful reproduction. Longevity is correlated with optimal natural immunity. Immunosenescence (aging of the immune system) is continuously influenced by chronic antigenic stimulation, such as infections. This explains why the probability of a long lifespan is improved in an environment of reduced pathogen burden. In the presence of low pathogen burden one can expect a balanced state of immune responses and alter the chances of having advanced inflammatory responses
Older persons have higher autoimmunity but a lower prevalence of autoimmune diseases. A possible explanation for this is the expansion of many protective regulatory mechanisms highly characteristic in the elderly. Of note is the higher production of peripheral T-regulatory cells.
The frequent development of autoimmunity in the elderly was suggested to take place in part due to the selection of T cells with increased affinity to self-antigens or to latent viruses. These cells were shown to have a greater ability to be pro-inflammatory, thereby amplifying autoimmunity. During aging, thymic T-regulatory cell output decreases in association with the loss of thymic capacity to generate new T cells. However, to balance the above mentioned autoimmunity and prevent the development of autoimmune diseases, there is an age-related increase in [peripheral T-regulatory cells]. It remains unclear whether this is an age-related immune dysfunction or a defense response. Whatever the reason, the expansion of T-regulatory cells requires payment in terms of an increased incidence of cancer and higher susceptibility to infections.
HMGA1 AS A POTENTIAL COMMON MECHANISM IN CANCER
Friday, May 3, 2013
Any mechanism that appears common to all cancers, or even just a wide range of cancers, is worth examination to see if it might serve as the basis for a therapy. Here is an example of speculative research of this nature:
[Researchers] have identified a gene that, when repressed in tumor cells, puts a halt to cell growth and a range of processes needed for tumors to enlarge and spread to distant sites. The researchers hope that this so-called "master regulator" gene may be the key to developing a new treatment for tumors resistant to current drugs. "This master regulator is normally turned off in adult cells, but it is very active during embryonic development and in all highly aggressive tumors studied to date. Our work shows for the first time that switching this gene off in aggressive cancer cells dramatically changes their appearance and behavior."
Genes in the master regulator's family, known as high mobility group or HMG genes, [are] essential for giving stem cells their special powers, and that's no coincidence. [Many] investigators consider cancer cells to be the evil twin of stem cells, because like stem cells, cancer cells must acquire special properties to enable the tumor to grow and metastasize or spread to different sites.
[Researchers applied techniques to block the HMGA1 gene] to several strains of human breast cancer cells in the laboratory, including the so-called triple negative cells - those that lack hormone receptors or HER2 gene amplification. Triple-negative breast cancer cells tend to behave aggressively and do not respond to many of our most effective breast cancer therapies. The team [found] that the cells with suppressed HMGA1 grow very slowly and fail to migrate or invade new territory like their HMGA1-expressing cousins. The team next implanted tumor cells into mice to see how the cells would behave. The tumors with HMGA1 grew and spread to other areas, such as the lungs, while those with blocked HMGA1 did not grow well in the breast tissue or spread to distant sites.
A SKEPTICAL VIEW OF MITOCHONDRIAL DNA DAMAGE AND AGING
Thursday, May 2, 2013
Not all researchers are presently convinced that enough evidence exists to place mitochondrial DNA damage front and center as an important cause of aging. I would agree that the tools and measurements discussed below leave some room for argument over what they mean, but at this time the research community is very close to being able to repair mitochondrial DNA, not just talk about it. Thus I think that the best approach for the next few years is to actually go ahead and repair the damage in laboratory animals, and see what happens - that should settle the debate one way or another.
Protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage is well known to be necessary to longevity. The relevance of mitochondrial DNA (mtDNA) to aging is suggested by the fact that the two most commonly measured forms of mtDNA damage, deletions and the oxidatively induced lesion 8-oxo-dG, increase with age. The rate of increase is species-specific and correlates with maximum lifespan.
It is less clear that failure or inadequacies in the protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage are sufficient to explain senescence. DNA containing 8-oxo-dG is repaired by mitochondria, and the high ratio of mitochondrial to nuclear levels of 8-oxo-dG previously reported are now suspected to be due to methodological difficulties. Furthermore, [mice lacking the MnSOD natural antioxidant] incur higher than wild type levels of oxidative damage, but do not display an aging phenotype. Together, these findings suggest that oxidative damage to mitochondria is lower than previously thought, and that higher levels can be tolerated without physiological consequence.
A great deal of work remains before it will be known whether mitochondrial oxidative damage is a "clock" which controls the rate of aging. The increased level of 8-oxo-dG seen with age in isolated mitochondria needs explanation. It could be that a subset of cells lose the ability to protect or repair mitochondria, resulting in their incurring disproportionate levels of damage. Such an uneven distribution could exceed the reserve capacity of these cells and have serious physiological consequences. Measurements of damage need to focus more on distribution, both within tissues and within cells. In addition, study must be given to the incidence and repair of other DNA lesions, and to the possibility that repair varies from species to species, tissue to tissue, and young to old.
In this context, you might also look at the membrane pacemaker theory regarding oxidative damage to mitochondria and longevity differences between species. It places an emphasis on resistance to damage and the consequences of damage over the actual levels of damage.
PROTECTING CRYONICS PATIENTS
Thursday, May 2, 2013
A short article on the need to remember that cryopreserved people are not gone in the same way that the dead are gone, and their interests are served by the maintenance of some form of continued connection to society:
Anyone who has ever reflected on the fragility of human life and the seemingly inevitable rise and fall of complex societies cannot fail to be concerned about the fate of patients in cryopreservation. Cryonics organizations have learned from the early days and abandoned the practice of accepting patients without complete prepayment - a practice that almost invariably guarantees a tragic loss of life when family members or the cryonics organization can no longer afford to care for them. Alcor has given a lot of thought to the financial and legal requirements of keeping patients in cryopreservation but it is understandable that people question the prospect of cryonics patients making it to the time where a suitable treatment of their disease will be available.
This challenge is further exacerbated by the fact that cryonics patients do not have the legal standing that ordinary human beings (or patients) enjoy. [The] first step to protect cryonics patients is to strengthen your cryonics organization and the legal and logistical structures that have been erected to keep them in cryopreservation. But almost just as important is to give people who have not made cryonics arrangements themselves reasons to protect them. In the case of surviving family members that is usually not a challenge but time may eventually pass the direct descendants of those people by as well.
One important practice that can be strengthened is to give these people a face. Cryopreserved persons are not just a homogenous group of anonymous people (unless they chose to be so!) but are our friends, family members, and patients who would like their story to be told. Fortunately, in the age of the internet this has become a lot easier. Social networking websites like Facebook retain the profiles of deceased and cryopreserved persons unless the family requests removal. Cryonics organizations themselves can offer opportunities for members, friends, and family members to maintain their presence online.
A REVIEW OF ADENYLYL CYCLASE TYPE 5 AND LONGEVITY IN MICE
Wednesday, May 1, 2013
Gene therapy to remove adenylyl cyclase type 5 (AC5) was shown to increase mouse longevity a few years back, and researchers have since been working to better understand the mechanisms involved. Like many longevity mutations, this gene is involved in many crucial low-level cellular processes, and researchers are interested in producing drugs to mimic some of the effects of a full gene therapy:
G-protein coupled receptor/adenylyl cyclase (AC)/cAMP signaling is crucial for all cellular responses to physiological and pathophysiological stimuli. There are 9 isoforms of membrane-bound AC, with type 5 being one of the two major isoforms in the heart. Since the role of AC in the heart in regulating cAMP and acute changes in inotropic and chronotropic state are well known, this review will address our current understanding of the distinct regulatory role of the AC5 isoform in response to chronic stress.
Transgenic overexpression of AC5 in cardiomyocytes of the heart (AC5-Tg) improves baseline cardiac function, but impairs the ability of the heart to withstand stress. For example, chronic catecholamine stimulation induces cardiomyopathy, which is more severe in AC5-Tg mice, mediated through the AC5/SIRT1/FoxO3a pathway.
Conversely, disrupting AC5, i.e., AC5 knockout (KO) protects the heart from chronic catecholamine cardiomyopathy as well as the cardiomyopathies resulting from chronic pressure overload or aging. Moreover, AC5-KO results in a 30% increase in healthy lifespan, resembling the most widely studied model of longevity, i.e., calorie restriction. These two models of longevity share similar gene regulation in the heart, muscle, liver and brain that are both protected against diabetes and obesity. A pharmacological inhibitor of AC5 also provides protection against cardiac stress, diabetes and obesity. Thus, AC5 inhibition has novel, potential therapeutic applicability to several diseases, not only in the heart, but also in aging, diabetes and obesity.
ON EXTENDING MOUSE LONGEVITY
Wednesday, May 1, 2013
Here is a popular science article on the many ways to extend life in laboratory mice, and the relevance of that research to human health and longevity:
Biologists have successfully extended the life spans of some mice by as much as 70%, leading many to believe that ongoing experimentation on our mammalian cousins will eventually lead to life-extending therapies in humans. But how reliable are these studies? And do they really apply to humans?
Many scientists will tell you that "mice are not people" which is true of course. It is also true that we have cured cancer many times in mice with therapies that do not work in humans, so we must be careful about saying that interventions that work in mice will be directly translatable to humans. But at the same time, functional life extension therapies in mice do hold prospects for human longevity. Extending the lifespan of a mouse that normally lives only three years to five by applying a treatment late in its life could capture the imagination of many. "In this day of the Internet, everyone would be able to view video clips of mice the equivalent of 120 human years in age - healthy, active and being social with their fellows.This would do something, I think, to the human psyche that would enable much more rapid development of interventions for humans, hence the reason for the Methuselah Mouse Prize which is designed to create this result."
Near everything demonstrated to date to extend life in mice has been a form of gene therapy or metabolic manipulation. It changes the pace of aging, but isn't rejuvenation. To create longer lives [than the present best efforts in mice], you need to work on rejuvenation attained by repairing the cell- and tissue-level damage that causes aging, not just finding ways to gently slow aging by slowing down the pace at which that damage accumulates. The future of mouse longevity is SENS (Strategies for Engineered Negligible Senescence), which is a radically different approach to any of the work currently extending life in mice.
GROWTH HORMONE AND IGF-1 IN AGING
Tuesday, April 30, 2013
The longest lived mice are those that have been altered to remove growth hormone or growth hormone receptors. In humans there is an analogous population of natural mutants, their condition known as Laron syndrome, who, like the mice, seem resistant to cancer and type 2 diabetes. They do not appear to live significantly longer than the rest of us, but that doesn't rule out modest extension of life - the data is lacking to say either way at this time.
Secretion of growth hormone (GH), and consequently that of insulin-like growth factor 1 (IGF-1), declines over time until only low levels can be detected in individuals aged ≥60 years. This phenomenon, which is known as the 'somatopause', has led to recombinant human GH being widely promoted and abused as an antiageing drug, despite lack of evidence of efficacy.
By contrast, several mutations that decrease the tone of the GH/IGF-1 axis are associated with extended longevity in mice. In humans, corresponding or similar mutations have been identified, but whether these mutations alter longevity has yet to be established. The powerful effect of reduced GH activity on lifespan extension in mice has generated the hypothesis that pharmaceutically inhibiting, rather than increasing, GH action might delay ageing. Moreover, mice as well as humans with reduced activity of the GH/IGF-1 axis are protected from cancer and diabetes mellitus, two major ageing-related morbidities.
Here, we review data on mouse strains with alterations in the GH/IGF-1 axis and their effects on lifespan. The outcome of corresponding or similar mutations in humans is described, as well as the potential mechanisms underlying increased longevity and the therapeutic benefits and risks of medical disruption of the GH/IGF-1 axis in humans.
IGF1R LEVELS IN THE BRAIN CORRELATE WITH SPECIES LIFE SPAN
Tuesday, April 30, 2013
The mechanisms of insulin signaling are one of the better studied metabolic determinants of longevity, though as for all such things it is a very complex system, not yet fully understood, and there a lot of debate and uncertainty in the resulting science. New data continues to roll in, however, here looking at variations of levels of the receptor for insulin-like growth factor 1 (IGF1R) in various different rodent species:
The insulin/insulin-like growth factor signaling (IIS) pathway is a major conserved regulator of aging. Nematode, fruit fly and mouse mutants with reduced IIS signaling exhibit extended lifespan. These mutants are often dwarfs leading to the idea that small body mass correlates with longevity within species. However, when different species are compared, larger animals are typically longer-lived. Hence, the role of IIS in the evolution of life history traits remains unresolved.
Here we used comparative approach to test whether IGF1R signaling changes in response to selection on lifespan or body mass and whether specific tissues are involved. The IGF1R levels in the heart, lungs, kidneys, and brains of sixteen rodent species with highly diverse lifespans and body masses were measured. [We] report that IGF1R levels display strong negative correlation with maximum lifespan only in brain tissue and no significant correlations with body mass for any organ. The brain-IGF1R and lifespan correlation holds when phylogenetic non-independence of data-points is taken into account. These results suggest that modulation of IGF1R signaling in nervous tissue, but not in the peripheral tissues, is an important factor in the evolution of longevity in mammals.
CALORIE RESTRICTION AND CALORIE RESTRICTION MIMETICS
Monday, April 29, 2013
Today I noticed this very readable open access paper that reviews calorie restriction research and ongoing efforts to produce drugs that can mimic some of the beneficial effects of calorie restriction on health and longevity. It can be downloaded in PDF format from the journal website:
Everyone desires a long and healthy life, and many researchers have investigated methods to overcome and to retard the aging process. The most well defined intervention of retarding aging is caloric restriction. Caloric restriction, also known as dietary restriction, is the reduction of food intake without malnutrition. Experimentally, caloric restriction means a reduction in calorie intake by 10-30% when compared to an ad libitum diet. Lifespan extension in response to caloric restriction is thought to be caused by a decreased rate of increase in age-specific mortality. It is widely believed that caloric restriction delays the onset of age-related decline in many species, as well as the incidence of age-related diseases such as cancer, diabetes, atherosclerosis, cardiovascular disease, and neurodegenerative diseases. Caloric restriction affects the behavior, animal physiology, and metabolic activities such as modulation of hyperglycemia and hyperinsulinemia, as well as increases insulin sensitivity.
Reductions of protein source in the diet without any changes in calorie level have been shown to have similar effects as caloric restriction. Furthermore, restriction of individual amino acids has been shown to induce lifespan extension in some species, especially methionine restriction. Moreover, the restriction of tryptophan is believed to have a positive effect on longevity. Thus, several researchers have stated that this phenomenon occurs as a result of dietary restriction, not caloric restriction. However, other studies have indicated that protein and/or methionine restriction is not involved in the caloric restriction-induced lifespan extension.
THE BURRILL AND BUCK AGING MEETING, MAY 20TH 2013
Monday, April 29, 2013
Here is a pointer to the website for a forthcoming conference to be held at the Buck Institute for Research on Aging in California. It is one of the many signs indicating that large, conservative financial entities like Burrill & Company are becoming more interested in longevity science:
Around the world, lifespans are increasing and populations are aging. This demographic shift presents opportunities for drug and device developers, as well as significant challenges for healthcare systems and payers. Diseases of aging are among the costliest and most intractable diseases we face. These include heart disease, stroke, cancer, neurological disease, pulmonary disease, and diabetes. While policy makers across the globe have taken steps to look for ways to restrict spending, others are turning to innovative approaches that can keep people healthy and allow them to live independently longer. Please join us at this inaugural Burrill & Buck Aging Meeting as we explore the consequences of aging, how therapeutics in development seek to address chronic diseases related to aging, and how innovative approaches from regenerative medicine to digital health stand to change our notion of what it means to grow old.