Fight Aging! Newsletter, October 3rd 2016

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

This content is published under the Creative Commons Attribution 3.0 license. 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!

To subscribe or unsubscribe please visit:


  • Calorie Restriction Reduces Age-Related Weakening of Blood Vessels
  • Newton was an Alchemist
  • Does Cellular Reprogramming in Fact Produce Mitochondrial Rejuvenation?
  • A Copy of the Self: Today's Airy Philosophy is Tomorrow's Practical Concern
  • Use of a Mitochondrially Targeted Antioxidant Fails to Reduce Sarcopenia
  • Latest Headlines from Fight Aging!
    • A Discussion of the Effects of Calorie Restriction
    • Calorie Restriction and Protection Against Age-Related Neurological Disorders
    • ERK Inhibition Proposed as a Target for Muscle Regeneration
    • Visceral Fat Harms Cardiovascular Health and Increases Risk of Disease
    • Speeding up Drug Discovery for Geroprotectors
    • Assessing the Brains of Supercentenarians
    • Epigenetic Clock Data from a Larger Study Population
    • Ten Years of Induced Pluripotency
    • No Correlation of Telomere Length with Longevity in Nematodes
    • Alternate Day Fasting Slows Progression of Glaucoma in an Animal Model

Calorie Restriction Reduces Age-Related Weakening of Blood Vessels

Since calorie restriction is the topic for the day so far, I thought I'd finish up by pointing out a recent paper that examines just one of the many concrete benefits that are produced through the practice of calorie restriction. In this case the focus is on blood vessel integrity, and the researchers demonstrate that a low calorie diet in mice reduces the risk of suffering an aneurysm, a localized weakening and consequent distortion of blood vessel walls. Aneurysms in major blood vessels ultimately lead to rupture and bleeding that is far more often fatal than survivable. Larger aneurysms in the brain can cause significant issues even without rupturing because they displace neural tissue, possibly disrupting vital functions as a result.

It isn't too difficult to walk through what is known of the various contributions that increase the risk of aneurysm, and the reasons why that risk rises with age. The first place to start is hypertension, increased blood pressure. Greater pressures means that ever lesser degrees of structural weakness will fail and bulge out into an aneurysm. Hypertension appears to be largely driven by stiffening of blood vessels, as the cardiovascular system reacts incorrectly to the feedback it is given by stiffened vessels. This loss of elasticity is in turn a consequence of cross-linking in the extracellular matrix of blood vessel walls, one of the fundamental forms of damage described in the SENS rejuvenation research portfolio. The normal processes of metabolism generate hardy sugar compounds that can link the complex collagen macromolecules of the extracellular matrix. The structure and movement of those macromolecules determines tissue characteristics such as elasticity, and cross-linking degrades that flexibility to produce stiffening. Other contributions to vascular stiffening include calcification in blood vessel walls and various secondary consequences of the chronic inflammation that accompanies aging, disrupting the signaling involved in blood vessel constriction.

Another group of mechanisms worth emphasizing are those that lead to atherosclerosis: damaged lipids in the bloodstream, such as those produced as a result of the harmful actions of cells with age-related mitochondrial damage, can cause an overreaction when they lodge in blood vessel walls. This produces lesions in which inflammation and immune cell death runs amok, growing into fatty plaques in the blood vessel wall. One of the ways in which such an atherosclerotic plaque can prove fatal is through weakening the blood vessel wall sufficiently for an aneurysm to develop and then rupture. Another is for the plaque to break apart and block a blood vessel elsewhere. Either way, the consequences are unpleasant. To the degree that atherosclerosis is a type of immune overreaction, it is accelerated by the rising levels of chronic inflammation that accompany aging.

Almost all of these processes are modestly reduced in magnitude while an individual is practicing calorie restriction. Inflammation is reduced, mitochondrial function improved, the immune system works more effectively to remove problem cells, and cells do a better job of internal quality control. Other environmental influences on the constriction of blood vessels are improved. Since calorie restriction is known to slow near all measures of aging, it perhaps isn't surprising to see it also reducing aneurysm risk. This is all relative, of course: despite the fact that calorie restriction produces perhaps the largest available long-term benefits for basically healthy individuals, you nonetheless can't reliably diet your way to a life span of a century. Rejuvenation therapies are on the horizon, however, and thus it is perhaps wise to pay attention to the few choices you can make now that are reliable and proven in their effects, likely to add a few years of health to your life span. Missing out by a few years when you could have benefited would be a terrible thing. Unfortunately, beyond calorie restriction and exercise there is little worth the candle at the moment, given the balance of evidence: efforts beyond the health basics are better directed to speeding progress towards human rejuvenation, helping the development of therapies that can repair the molecular damage that causes aging.

Consuming Fewer Calories Reduces the Risk of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a localized enlargement of the main artery in the abdomen caused by a weakening of the blood vessel wall. With over three million cases per year in the US, preventing the development of AAA is crucial because, if the aneurysm bursts, the mortality rate can be as high as 80%. The risk of developing AAA increases with age and can be exacerbated by other factors such as smoking. Calorie restriction has been shown to have a variety of health benefits in mice and humans due to its far-reaching effects on the body's metabolism. Researchers wondered whether the risk of AAA might be reduced by a calorie-restricted diet. The researchers placed mice prone to developing AAA on a calorie-restricted diet for 12 weeks and found that the animals were less likely to develop aneurysms than control mice fed a normal diet. The calorie-restricted mice also showed lower rates of AAA rupture and death.

The researchers determined that calorie restriction reduced the levels of an enzyme called MMP2 that degrades the protein matrix surrounding blood vessels. This was because, after 12 weeks of reduced calorie intake, vascular smooth muscle cells in the wall of the aorta up-regulated a metabolic sensor protein called SIRT1, which can epigenetically suppress multiple genes, including MMP2. The researchers found that calorie restriction was unable to reduce MMP2 expression and the incidence of AAA in mice whose vascular smooth muscle cells lack SIRT1. The study suggests that reducing calorie intake can protect mice from AAA by up-regulating SIRT1.

Calorie restriction protects against experimental abdominal aortic aneurysms in mice

Abdominal aortic aneurysm (AAA), characterized by a localized dilation of the abdominal aorta, is a life-threatening vascular pathology. Because of the current lack of effective treatment for AAA rupture, prevention is of prime importance for AAA management. Calorie restriction (CR) is a nonpharmacological intervention that delays the aging process and provides various health benefits. However, whether CR prevents AAA formation remains untested. In this study, we subjected Apoe-/- mice to 12 weeks of CR and then examined the incidence of angiotensin II (AngII)-induced AAA formation. We found that CR markedly reduced the incidence of AAA formation and attenuated aortic elastin degradation in Apoe-/- mice. The expression and activity of Sirtuin 1 (SIRT1), a key metabolism/energy sensor, were up-regulated in vascular smooth muscle cells (VSMCs) upon CR. Importantly, the specific ablation of SIRT1 in smooth muscle cells abolished the preventive effect of CR on AAA formation in Apoe-/- mice. Mechanistically, VSMC-SIRT1-dependent deacetylation of histone H3 lysine 9 on the matrix metallopeptidase 2 (Mmp2) promoter was required for CR-mediated suppression of AngII-induced MMP2 expression. Together, our findings suggest that CR may be an effective intervention that protects against AAA formation.

Newton was an Alchemist

As I'm sure many people are aware these days, with the greater availability of historical materials and their analysis, Isaac Newton was as much alchemist as scientist. His worldview encompassed mysticism, mathematics, and cosmology in equal parts, a function of his time. You can't really pick apart Newton the scientist from Newton the mystic, Newton of the equations and proofs from Newton of the search for the philosopher's stone. A person is a fusion, not a collection of parts. You also can't paint Newton as somehow distinct from his peers in this - he was an outlier in his intelligence, his vision, and his work ethic, not in his views on alchemy. Keep this in mind as a framing device; I point it out because the mix of futile, magical endeavors and the sound application of science, both pursued with equal vigor, is far from left behind in Newton's era. It continues today, and it is of great relevance to progress (or lack thereof) the field we all care about, advancing the state of the art in living longer, healthier lives.

I, and others in our community, believe that the "anti-aging" marketplace as it stands is both terrible and an opportunity. Ultimately if the good can chase out the bad, then these are people with clinics, funds, and the desire to do something about aging, exactly those who could do a great deal of good in pushing forward research, development, and clinical availability if they so chose. As real rejuvenation therapies emerge, the entrepreneurs of that marketplace will stop trying to sell products based on cherry-picked scientific studies, outright lies, and magical thinking. You can't make money selling tables that fall apart when the people next door sell tables that work. The same applies to medicine. Consider what a medical market with even partially effective treatments looks like: no-one today makes much of a business selling charms against heart disease. For sure, it exists, but will-workers and traveling tinkers certainly aren't the first port of call for the average individual - patients seek out doctors and clinicians in the knowledge that there are treatments that can product useful results. The end result is never an end to fraud and superstition, but the crushing of it into a tiny corner of economic activity. I suspect that this is going to be a drawn out and messy process for longevity science, however, just as it has been elsewhere in the past. Will we see clinics selling working rejuvenation therapies such as senescent cell clearance infusions in a package with nonsense like apple stem cell skin cremes? No doubt. Caveat emptor, just as true ten years from now as it is today.

Many folk feel that the "anti-aging" market is too much of a threat to have anything to do with. That it will not reform and will poison whatever it touches. Certainly there are people in there with that mix of adherence to mysticism and science that has characterized many figures in the history of science and technology, whether giants like Newton or the rank and file who get far lesser mention in the pages of history. The Life Extension Foundation principals are comfortable pushing useless nonsense on the one hand (overhyped supplements based on dubious research results taken out of context, anything that Suzanne Somers has to say about health, and so forth) while on the other hand helping to fund stem cell research trials and SENS-like programs of development such as thymic regeneration. They've given a good deal more money to those worthy causes than I have. Nonetheless, the alchemy, the alchemy. It is painful. There is a certain anxiety that people we might persuade to the cause of human rejuvenation take in things like the recent RAAD Festival, and as a consequence throw out everything they see, baby and bathwater, as the author did here. When the first few samples raised up to the light for examination are evident nonsense, why check the others carefully?

A weekend watching the promise of immortality get sold and bought at the Revolution Against Aging and Death Festival

I was invited to attend RAAD after I wrote about people who want their pets to live forever. I was initially confused by the phrase "age reversal." As it turns out, RAAD sells something more audacious than pricey cosmetics or Li'l Brad Pitt. RAAD stands for Revolution Against Aging and Death. It sells the promise of eternal youth. Also, Suzanne Somers was going to be there. The people who organized RAAD are members of the Coalition for Radical Life Extension, which is the nonprofit offshoot of People Unlimited, a Scottsdale, Arizona-based group that describes itself as "a community of people living physical immortality." People Unlimited charges a monthly membership fee, and holds regular meetings where members swap antiaging tips and listen to guest speakers. The coalition's online mission statement shoehorns immortality into a historical narrative of moral and social progress. Radical life extensionists believe that eternal life will eventually be viewed as a sort of buried human right, as soon as they convince people that they're not delusional.

Though immortalists aren't mainstream, radical life extension has a burgeoning fan base in the tech industry. Along with Alphabet's Calico, which is a secretive Google spinoff focused solely on the study of aging, other prominent antiaging research labs and biotech firms have budded up among the techno-utopians. While the search for ways to stop aging and "cure" death is booming from a business perspective, the reality of biotech solutions for age-related problems is far more nuanced than the vision presented at RAAD, where researchers spoke in highly optimistic terms about progress just around the corner. Assuming that this research will lead to insight on how we age is one thing. Assuming it will free us from the bonds of mortality is an enormous leap. And so even within the community of researchers who study old age and life extension, immortalists are considered radical, and sometimes accused of peddling pseudoscience.

To cast the widest possible net for converts, RAAD touted many different twists on the concept of living forever. No one path to immortality was placed above another. There were many different denominations of immortalists present, with a patchwork of philosophies and goals: stem-cell facials, telomerase research, transhumanism, cryonics, brain uploading, cyborgism, vitamins, blood transfusions, marathon running, sex. After she ran through her spiel, Suzanne Somers sat down with Bill Faloon, another superstar within the life extension movement. Faloon founded the Life Extension Foundation in 1980, and he was ready to back up every last irresponsible word Somers uttered. "There is a tremendous amount of peer-reviewed literature to substantiate what Suzanne has said, including diet and health," Faloon said. Faloon applauded Peter Thiel for donating money to antiaging causes. Thiel has donated to gerontologist Aubrey de Grey, who founded the SENS (Strategies for Engineered Negligible Senescence) Research Foundation. De Grey is a British man with objectively too much beard who is famous among futurists and infamous among scientists for claiming that the first person who will live to a thousand years old is alive today. He's good at raising money for antiaging research and courting celebrities to join his cause. SENS has an ad campaign that features Steve Aoki, Herbie Hancock, Edward James Olmos, and the guy who played Little Carmine on The Sopranos.

This is the messiness of the business of persuasion in action. Though I have to say that the author here is evidently smart enough to realize there's something down there at the science end of the pool, but chose to write the article this way anyway rather than working harder at the more interesting picture that is presented. Work on telomerase is arguably pretty important in aging research. Cryonics is a logical response to death in an age of technological progress. Aubrey de Grey's SENS Research Foundation is serious business, a part of the very real, very promising road to working rejuvenation therapies. Suzanne Somers on the other hand is a great illustration of the fact that business fundamentals trump everything else, including having products that actually work, or making claims that are actually sound, true, and supported by evidence. The Life Extension Foundation's Faloon has a foot in both camps. There you have the span from science to mysticism in just three people.

This is what human endeavor looks like when existing products have very marginal effects, and thus fraud is both easier to carry out and harder to suppress. But as I noted above, that will start to change soon enough. Senescent cell clearance will be in clinics five to ten years from now, alongside before and after DNA methylation biomarkers of biological age, and that will be indisputably effective in comparison to everything else out there claimed to have an impact on aging. From there matters might start to clean up somewhat, as the first of the frauds and the mystics begin to exit, stage left. Where am I going with this? Well, it would be great if everyone thought more or less the way I do about longevity science, but you have to live in the world that is, not the world that you'd like to exist. You work with the hand you've been dealt. Newton was an alchemist, and fundamentals of human nature haven't changed since then. The people getting things done today will inevitably tend to spend only a fraction of their time on projects and publicity that you or I might consider to be the most important items on the list, and many will embrace mysticism and counterproductive activities along the way. This is the way things go. It is certainly far from ideal, but still we move ahead. The end goal of a "anti-aging" community even halfway converted and backing the right approaches to human rejuvenation is, I think, too much of a potential boost to throw away because of the present situation. That means building the bridges now, in exactly the same way that bridges must be built to Big Pharma, governments, and other relevant institutions that are themselves less than ideal.

Does Cellular Reprogramming in Fact Produce Mitochondrial Rejuvenation?

The reprogramming of ordinary somatic cells into induced pluripotent stem cells, capable in principle of then generating any other type of cell, was a major advance for cell biology and its application to medicine. It is still sufficiently recent for the implications and uses still to be a work in progress. One of the more interesting observations to emerge from the recent years of experimentation is that this reprogramming appears to erase some aspects of mitochondrial aging. Take fibroblasts with damaged mitochondria from a skin sample from an aged individual, reprogram them to generate a population of induced pluripotent stem cells, differentiate those stem cells into a new set of fibroblasts, and the resulting cell population has dramatically improved mitochondrial function. One possibility is that reprogramming triggers some aspects of the comprehensive repair programs that take place very early in embryonic development, wiping away as much of the parental molecular damage as possible. Parents are old and babies are born young, so something of this ilk must be hidden away somewhere in the repertoire of cellular behavior. That isn't to say it can be usefully applied in adults, of course: there are any number of vital, intricate structures in our organs, the brain particularly, that would probably be fatally disrupted by the operation of such a program. Time will tell.

Is this apparent mitochondrial rejuvenation actually mitochondrial rejuvenation, however? Is it fixing the all-important damage to mitochondrial DNA, for example? Every cell has hundreds of mitochondria, the descendants of ancient symbiotic bacteria, complete with a leftover fragment of the original DNA that still encodes a range of necessary proteins used in mitochondrial functions. Mitochondria still divide like bacteria to make up their numbers, even though they are treated just like any other cellular component and broken down for recycling when damaged. Their most important function is the generation of energy store molecules to power cellular operations, but this process produces oxidizing molecules as a side-effect. They damage the cellular machinery they react with, and the most vulnerable target is the mitochondrial DNA right next door. Most oxidative damage to proteins and DNA in cells is rapidly repaired, but mitochondrial DNA isn't as well protected as the DNA in the cell nucleus. Further, some forms of mitochondrial DNA damage, such as large deletions, can produce mutant mitochondria that are both dysfunction and resistant to being culled by cellular quality control mechanisms. They quickly outcompete the normal mitochondria, and a cell taken over in this way becomes dsyfunctional itself, carrying out a range of bad behavior that contributes to the progression of aging. Thus mitochondrial DNA damage is an important topic; if researchers observe what looks like mitochondrial rejuvenation, then the quality of the mitochondrial DNA is a key question.

The authors of this commentary discuss a paper published earlier this year that argues against repair of mitochondrial DNA in the course of cellular reprogramming. If confirmed that means that a potential shortcut to allow cell therapies to better treat the diseases of aging may not in fact exist: dealing with mitochondrial DNA damage when using a patient's own cells is still required, one way or another. The favored method is that outlined in the SENS proposals, using gene therapy to move critical mitochondrial genes into the cell nucleus. There are other possible approaches, though none of those seem to be as far along towards clinical application. While one door closes, another opens, however. As pointed out below, the preservation of mitochondrial damage might indicate that reprogramming as it presently stands, in which only a tiny number of cells are successfully converted, may be a good way amplify rare mutations in cell samples. That in turn might help with the still challenging task of putting reliable numbers to the degree to which mitochondrial DNA is damaged in old cells.

Aging vs. rejuvenation: reprogramming to iPSCs does not turn back the clock for somatic mitochondrial DNA mutations

The process of cellular reprogramming is believed to be able to "turn back the developmental clock" by allowing somatic cells to acquire a state that is normally associated only with embryonic stem cells (ESCs). Indeed, human induced pluripotent stem cells (iPSCs) can be obtained from aged individuals and still show the key properties of ESCs, including self-renewal, elongated telomeres, and round-shaped mitochondria with underdeveloped cristae. However, it remained to be determined whether reprogramming to pluripotency could actually erase aging-associated signatures and thus represent a rejuvenation route. A new paper now clearly demonstrates that iPSCs not only do not erase the signs of aging but, due to their clonal origin, may even reveal aging-related defects in the mitochondrial DNA (mtDNA) that were not detectable in the whole parental tissues.

Using iPSCs derived from both skin fibroblasts and peripheral blood mononuclear cells (PBMCs) researchers have shown that all iPSCs exhibited mtDNA mutations that could not be observed in the whole-tissue DNA extracts of the parental cells. These mutations were originally considered as negative by-products of reprogramming as a consequence of oxidative stress-mediated genomic damage. However, it was demonstrated that also skin fibroblasts grown as individual clones exhibit mtDNA mutations that are not seen in the pooled fibroblast population. Hence, individual cloned fibroblasts and iPSCs may both represent the progeny of a single parental fibroblast cell, thereby enabling the detection of mtDNA mutations that were already present in the original fibroblast population but remained undetectable due to their relatively low presence. Several studies indicate that mtDNA mutations, including large-scale deletions, increase with aging. In accordance, researchers detected increased presence of mtDNA mutations in fibroblasts and iPSCs derived from aged individuals compared to young individuals. Moreover, the identified mutations in somatic cells and derived iPSCs were mostly located in coding genes, while ESCs displayed mtDNA variants primarily within the non-coding D-loop. This gives further support to the notions that the majority of mtDNA alterations seen in adults is of somatic rather than embryonic origin.

An important point to be addressed was the functional consequence of the detected mtDNA mutations. The presence of mtDNA alterations that were not seen in the pooled parental fibroblasts were previously found to not cause major bioenergetic defects, as all generated iPSCs could efficiently undergo the extensive metabolic shift that is associated with cellular reprogramming. However, detailed analyses unveil diminished metabolic function in iPSCs carrying high heteroplasmic mtDNA mutations. Hence, in order to correctly employ patient-derived iPSCs for disease modeling and therapeutic studies, it will be imperative to include the detection of mtDNA integrity as part of the basic characterization toolkit. This will be especially relevant when dealing with patients of advanced age who may harbor increased amount of mtDNA mutations. Overall, this work strongly confirms that, in addition to nuclear genome integrity, mitochondrial genome integrity will become a key parameter to investigate for all medical applications of iPSCs. Furthermore, it highlights the strength of single-cell studies, which may reveal the real biological variability that pooled population studies have so far prevented to be identified. In conclusion, in order to allow faithful and meaningful discoveries, future analysis of iPSCs and their derivatives should not shy away from mitochondrial genome monitoring and single-cell technology.

A Copy of the Self: Today's Airy Philosophy is Tomorrow's Practical Concern

The march of technology turns matters of philosophy into matters of practical action. The process of taking visions and making them concrete makes once airy hypotheticals relevant in everyday life. The theoria of the ancient Greeks becomes praxis. What if I could talk to my compatriot now journeyed to the far side of the sea? What if the years of men and women were not limited as the gods decreed by way of the example of Tithonus? What if I could see the very smallest building blocks of the stones and the plants? How could a city of ten million ever be governed? How would men and women live were there not the need for near all to work the land? This process continues today, and at a much accelerated pace as new capabilities emerge with each passing generation. A transition lies ahead, however. Some of the new technologies of the rest of this century will be different from those of the past in one very important way: they will allow the human mind and human nature to be changed, to be copied, to be reconstructed in software and machinery other than that of our present biology. This prospect gives weight to a range of important philosophical questions both in the futurist community and among those who carry out practical work that contributes to this future.

The question for today is this: is an exact copy of you also you? As a consideration, this is of absolutely no practical value to most people today - unless either (a) you happen to think that the Many Worlds interpretation of quantum mechanics likely reflects reality, or (b) you are signed up for cryopreservation as an end of life choice. Even then only the latter group might choose to do something as a result of having a position on this topic. The reason that this question and the voluminous philosophical discussion surrounding it are of limited perceived value to the average individual is, of course, that we cannot create copies of people. Not now, and not for a few decades yet. Most of those reading this now in 2016 will, however, live to see minds copied. Reverse engineering the human brain seems to be to be the most plausible road to the creation of artificial general intelligence. Unlike the other approaches, it quite clearly requires only the combination of sufficiently large amounts of processing power and sufficiently good understanding of the molecular biochemistry of the brain. The more of the former that is in hand the less of the latter that is needed, but both of these areas of human endeavor are moving forward at a fair pace. Praxis will start with tentative running copies of scanned neural architecture in the laboratory, and from there the process of research and development will be driven ever faster. The advantages inherent in being able to create new economic actors with a fraction of the resources needed prior to that point are enormous, and the societies that embrace this technology will dominate. By that time a position on whether a copy of you is also you will be a very necessary thing, and I don't think this is the far distant future we're talking about here. Once this revolution is well underway, and driven by economics, individuality will start to fray at the edges, and those who are comfortable with that fraying will take full advantage of it.

That is the future. But people who are signed up with cryonics providers really do need to have a position on this question now. The cryonics community is quite divided between those who believe that a copy of their preserved brain, running as an emulation, is a quite satisfactory form of survival, and those who want their original biological architecture repaired and restored. That all hinges on what you think about the ontological status of an exact copy of you. If rejuvenation research fails to deliver in time and you are forced into cryopreservation as the only viable backup plan that offers a shot at life again in the future, then your only defense against someone choosing to scan and emulate your mind - discarding your vitrified flesh along the way - is to request that this not happen. If you don't express a preference in a way that will last (a metal plate under the tongue?) then you are taking an additional chance on how the winds of culture and preference will turn in the years ahead. The part that concerns me is the economic angle I mentioned above; that it seems plausible that tremendous advantages will accrue to those who chose to abandon the concept that individuality is tied to matter and state, and instead become comfortable with both copying of the self and radical alteration of the mind from moment to moment.

As a longer examination of this divide insofar as it applies to cryonics today, I'll point out the article linked below, published earlier this year. I think the author doesn't quite get the division of views right, but it remains an interesting read. I'm a reanimator in his taxonomy, but certainly not possessed of any vitalist ideas about the necessity of a biological substrate for the human mind. It is perfectly possible to consider that the data of the mind can and will be copied and run in software on a practical basis, and still be quite attached to this present instance of the self, associated with its present set of matter, considering it a distinct and different individual from any hypothetical copy, running on a different set of matter. This instance of me is the self, the one that needs to survive for there to be a point to this exercise: the pattern that matters is this slowly changing set of atoms that moves forward through time with no major discontinuities. I might be generally well inclined towards a copy, should such a thing come to pass, but then we all tend to be generally well inclined towards people who share our views. That is about as far as it goes.

The Transporter Test and the Three Camps of Brain Preservation

People who are at least a little bit intellectually curious about making the brain preservation choice at the end of their lives are a small but growing demographic. It has been estimated at 1% of the population of most developed-world societies, and a likely smaller fraction in traditional societies. That's a small percentage, but a large number of individuals. We can also expect this group will grow as the cost and accessibility of brain preservation drops, and as validation that preservation preserves retrievable memories (and perhaps more) in animal models grows. The currently preservation-interested demographic can be easily divided into three camps, each with different expectations for the future. The folks in each camp don't always understand or talk to each other all that well, but they need to learn to get along. You'll probably grant that at some point in your future either you or your loved ones will find yourself contemplating, at least briefly, the major life choice of cryonics. Having to think about this topic may even happen earlier than you expect. Death has a way of surprising us.

Camp 1 - Reanimators

Reanimators either desire, or expect it will be necessary, to repair and reanimate (bring back to life) themselves in the form of biological bodies, in order to live again. They believe or expect, with a greater than 50% probability (and for some, essentially 100% probability), that their personal identity (personality and self-awareness) arises out of the unique physical and informational features of biology. Thus they think human minds need to be biological in order to exist. Reanimators hope to perfect a technology some call "reversible solid-state suspended animation," the ability to cryonically preserve and later reanimate human beings and brains. That is an exciting vision, and we can certainly expect some progress on that front. There are numerous examples of the new tissue and organ preservation strategies being tried in labs around the world, with the near-term goal of expanding tissue and organ banking in medicine.

Camp 2 - Uploaders

Uploaders are "patternists," meaning they believe or expect, with greater than 50% probability (and for some, essentially 100% probability), that the functional abilities (informational and computational patterns) of their biology are their true self, not their biology, which presently carries that pattern, and not their matter either, which changes constantly during their lives. Another way of defining an uploader is that they believe or expect that there is less than 50% probability that repair and reanimation of their biology or their matter will be necessary in order to wake up in the future. They expect instead to be scanned and uploaded, and wake up as a technological mind, inside some kind of technological body, in a future environment. This brain scanning and uploading technology is already much farther along than most people think. For example, neuroscience labs around the world are already using automated FIBSEM machines (a kind of electron microscopy) to scan and upload into computers detailed connectomes of small animal brains, including flies, zebrafish, and even parts of mouse brains. We don't yet understand how to read memories from these digital connectomes. But give it a little time.

Camp 3 - Uncertains

Uncertains as their name implies, don't yet buy the arguments of either of these two camps, which puts them firmly in a third camp. They talk about cryonics and brain preservation as an "experiment" or a "bet" that they'd much rather make, given the alternative experimental groups, that of either certain death or a religious afterlife. If asked, they might put the odds near 50/50 for reanimation being necessary for them to come back, or simply unknown. Some uncertains will grant that neuroscience and computer science now argue that human memories are stored in a small set of stable molecular features (most importantly, dendritic spines) in neural connectomes, and that if these are well-preserved at death, then our life's memories can very likely be scanned and uploaded to future computers, to share with our loved ones or the world. But they are typically agnostic on the question of whether all the brain's functions, including emotion, personality, and consciousness, are substrate-independent.

The Transporter Test

A good test of whether you are a reanimator, an uploader, or uncertain, and whether you have an instinctual bias to reanimation, as most folks do when they first engage with these ideas, is to ask the Transporter question, a test that uncovers your assumptions and biases with respect to the copy problem. Would you go through a Star Trek transporter (molecular scanner, disassembler, pattern storer, information beamer, and reassembler, using new molecules) if many others had done it, and claimed to still be themselves on the other end, and as far as you could tell they seemed the same? Or would you not go because you presently believe the process would cause your own death as your brain was being molecularly disassembled, and you believe your reassembled brain and body would be just some kind of unacceptable copy that only "thinks" it is you? This is a really deep question, and it depends on your view of the nature of personal identity. Consider that all three responses to this test are valid, from the point of view of members of each camp. If such a device were created, all three mental attitudes would be common, and all three would be socially reinforced as the right choice, by the members of each camp. So it should be obvious that each camp needs to learn to get along better, right?

Use of a Mitochondrially Targeted Antioxidant Fails to Reduce Sarcopenia

Regular readers will be at least passingly familiar with the commercial development of mitochondrially targeted antioxidant compounds that has taken place over the past decade. This initially attracted attention in this community because the evidence suggests that these molecules can modestly slow the progression of aging, though unfortunately not to the same degree as interventions like calorie restriction, which to my eyes at least means that serious life extension efforts are better directed elsewhere. The furthest advanced of these mitochondrially targeted antioxidants is the SkQ series of plastinquinones, currently being developed as a treatment for a few different conditions by Mitotech. It turned out that the effects on inflammatory eye conditions were considerably larger than the effects on aging, so that is the direction presently taken. Another of the compounds under development by a different set of researchers is SS-31; you'll find an introduction in the Fight Aging! archives. In the paper noted below, SS-31 is used to demonstrate that reducing oxidative stress in muscle cells doesn't slow the age-related loss of muscle mass and strength known as sarcopenia. This is a nice piece of work that might help focus future research efforts in more productive directions.

Given that straightforward antioxidants of the sort purchased in a supplement store either do nothing for health and aging or actually somewhat harm long term health, why would be expect antioxidants targeted to the mitochondria within the cell to be a different proposition? It helps to start by noting that the roles of oxidative molecules and antioxidants in the cell are manifold and complicated. Oxidative molecules cause damage by reacting with important protein machinery, but they are also used as signals. Too much is bad, and too little is bad. Exactly where there is too much or too little is also of great importance. Globally suppressing oxidative signaling via high levels of ingested antioxidants has negative effects like blocking the benefits of exercise, which depend upon that signaling. Mitochondria are central to all discussions of oxidative signaling, as they generate oxidative molecules as a result of their primary role as power plants, supplying energy store molecules to power the cell. Many of the genetic alterations and other interventions that modestly slow aging in laboratory species change mitochondrial function, either increasing or reducing the flux of oxidative molecules.

There are several likely ways in which altered mitochondrial output of oxidative molecules can affect long term health, that alteration achieved either by changing the rate at which such molecules are created, or by applying targeted antioxidants that soak them up immediately. Firstly there is hormesis: a slightly higher than usual output and the resulting damage can trigger greater and lasting repair and maintenance activities in the cell, leading to a net benefit. Or, alternatively, a lower level of output of oxidative molecules might just lead directly to less damage. Further, there are many other aspects of cellular metabolism that might run in ways better suited to a slower pace of aging if mitochondria generate either more or less oxidative molecules; that is poorly mapped and highly dependent on species, tissue, and circumstances. Lastly there is the important matter of mitochondrial DNA damage in aging. Mitochondrial dysfunction appears to be an important contribution to aging, and it is likely driven by mutational damage to DNA in the mitochondria caused by their own generation of oxidants. This DNA damage can produce mitochondria that are both dysfunctional and resistant to quality control. They quickly overtake a cell, and over the course of a lifetime ever more cells fall into this state. Their behavior contributes to degenerative aging in a range of ways, starting with the export of much larger amounts of oxidizing molecules into the surrounding tissues.

Thus rising levels of oxidative stress are considered important in many aspects of the progression of aging, but it is far from the only type of change, damage, and dysfunction taking place. So it shouldn't be a complete surprise to find that some conditions are not affected in the slightest by adjusting mitochondrial oxidant output, even when the indications suggested that outcome to be plausible enough to try. Metabolism is a ferociously complex business, incompletely understood, which is why bypassing its alteration in favor of identifying and fixing fundamental forms of damage should be a much more efficient approach to the treatment of aging and age-related conditions. We have a metabolism that works well when young, even it isn't fully understood, and researchers have a list of the fundamental, first cause differences between young and old tissues, so the goal should be to revert those differences and maintain the working system, rather than try to adjust it.

Mitochondrial ROS regulate oxidative damage and mitophagy but not age-related muscle fiber atrophy

Skeletal muscle is a major site of metabolic activity and is the most abundant tissue in the human body. Age-related muscle atrophy (sarcopenia) and weakness, characterized both by loss of lean muscle mass and reduced skeletal muscle function, is a major contributor to frailty and loss of independence in older people. Studies of humans indicate that by the age of 70, there is a ~25-30% reduction in the cross sectional area (CSA) of skeletal muscle and a decline in muscle strength by ~30-40%. Age-dependent loss of muscle mass and function has a complex aetiology and the primary biochemical and molecular mechanisms underlying this process have not been fully determined.

Oxidative stress has been suggested to be a key factor contributing to the initiation and progression of the muscle atrophy that occurs during aging. Consistent with a role of oxidative stress as a contributor to sarcopenia, studies have shown that genetic manipulations of redox regulatory systems can alter the aging process in muscle. Skeletal muscle decline with advancing age has been linked to an altered oxidative status of redox-responsive proteins and a number of studies have indicated a positive correlation between tissue concentration of oxidized macromolecules and life span including an increase in DNA damage, accumulation of oxidized proteins and increased levels of lipid peroxidation with age. In support of these findings recent quantitative proteomic approaches have further provided evidence that muscle aging is associated with a reduction in redox-sensitive proteins involved in the generation of precursor metabolites and energy metabolism, implying age-related redox changes as an underlying cause of age-related muscle atrophy.

Skeletal muscle produces reactive oxygen and nitrogen species (RONS) from a variety of subcellular sites and there is evidence that isolated skeletal muscle mitochondria exhibit an age-related increase in hydrogen peroxide (H2O2) production. Furthermore, muscle aging is associated with reduced mitochondrial oxidative-phosphorylation, reduced mitochondrial DNA (mtDNA) content, accumulation of mutated mtDNA, impaired mitophagy and increased mitochondrial permeability transition pore sensitivity, which are all proposed to contribute to the sarcopenic phenotype. Although cumulative oxidative stress has been proposed to induce age-associated reductions in mitochondrial function, this remains a controversial topic.

We and others have recently reported that pharmacological application of the mitochondria-targeted SS31 tetrapeptide can attenuate mitochondrial superoxide production in intact mitochondria of skeletal muscle fibers. This pharmacological approach complements genetic approaches, including those using targeted overexpression of the human catalase gene to mouse mitochondria. Such pharamacological agents may have substantial translational implications for the use and/or development of mitochondria-targeted antioxidants for treatment of human mitochondrial myopathies as well as mitochondrial reactive oxygen species (mtROS) mediated muscular dysfunctions. The purpose of the present study was to determine the effect of the mitochondria-targeted SS31 peptide on redox homeostasis in muscles of old mice, including mtROS and oxidative damage, mitochondrial content and mitophagy and on age-related muscle atrophy and weakness. Through this approach we aimed to determine the role of modified mitochondrial redox homeostasis on age-related loss of muscle mass and function.

Our findings demonstrated that a reduction in mtROS in response to SS31 treatment prevented age-related mitochondrial oxidative damage and improved mitophagic potential, but further demonstrated that changes in mitochondrial redox environment towards a more reduced state failed to rescue the sarcopenic phenotype associated with muscle fiber atrophy and loss of muscle mass and strength. This work has therefore identified that the age-related changes in mitochondrial redox potential play a key role in the loss of mitochondrial organelle integrity that occurs with aging, but are not involved in the processes of age-related muscle fiber atrophy.

Latest Headlines from Fight Aging!

A Discussion of the Effects of Calorie Restriction

Calorie restriction, reducing calorie intake while maintaining optimal levels of micronutrients, produces beneficial alterations in near all aspects of metabolism. It extends healthy life spans in near all species investigated to date, through this effect is much larger in short-lived species that have evolved a greater plasticity of life span in response to circumstances. In humans the consensus is that it might make a difference of a few years to overall life span, but it certainly greatly improves measures of health and lowers risk of age-related disease, suggesting the effect on healthspan is probably larger. Here, researchers discuss the effects of calorie restriction and some of the candidate calorie restriction mimetic drugs. It is a lengthy paper, but worth reading if you'd like a comprehensive overview of past investigations:

The aging process is undoubtedly the single most significant contributor to disease and death. Although this has been the inevitable outcome of all life on this planet, is aging an unavoidable consequence or can it be treated and potentially cured? As of yet this question remains unanswered, but many believe that the aging process is essentially a disease. Environmental conditions, including lifestyle, can greatly affect the rate of aging. For example, obesity or excessive ingestion of calories has been linked to increased incidents of age-related pathologies. Several lines of research indicate that certain behaviors can increase our health and potentially lifespan, such as exercise and regimes to improve cardiovascular function. One such intervention is the use of dietary/caloric restriction (CR); the reduced intake of calories/nutrients without causing malnutrition. In recent years, this observation has been verified across a large number of model organisms. These observations not only demonstrated an increase in the lifespan, but also in healthspan (time spent being healthy) of these organisms coincident with a significant decrease in age-related pathologies such as cardiovascular disease, diabetes and a number of cancers. For example, when fed a diet consisting of 35% of the ad libitum intake but enriched with vitamins and minerals, mice lived an average of 53 months, compared to 35 months in the control ad libitum-fed group.

Several drugs or naturally occurring compounds in food have been found to "mimic" the phenotypes of CR and could be potential alternatives to this somewhat difficult to follow dietary regime. An obvious first question: Do these compounds mirror the effects of CR? A large body of outstanding research focuses on the impact of CR and mimetics on autophagy in the regulation of longevity and in promoting apoptosis in cancer cells; however, the mechanism and impact on genome function (gene expression) and organization (epigenetic changes and physical genome folding) are less well understood. The oxidative damage attenuation hypothesis states that increased metabolism from high levels of nutrients/calories leads to higher rates of reactive oxygen species (ROS) and that lowering these levels will prevent lipid, protein and DNA damage. Damage such as this would lead to decreased function of cellular components as well as to increased rates of mutation. However, the other side of this hypothesis states that lower metabolic rates results in decreased rates of DNA damage and increased genome stability, and thus in fewer incidents of cancer. Although this is logical, some data does indicate that there is not a significant enough change in free radical production upon CR to significantly decrease ROS levels indicating that the benefits of CR might not be elicited through this mechanism. Although CR increases lifespan, it may not be due to a reduction of the ROS levels produced by mitochondria, but may result from an increase in the expression of enzymes that protect against these highly reactive molecules, reducing net oxidative stress. However, in D. melanogaster exposed to CR, no link between lifespan extension and increased resistance to oxidative stress has been found.

The altered glucose-insulin hypothesis indicates that CR causes a decrease in the circulating levels of both insulin and glucose, leading to decreased insulin signaling. This is based on observations that decreased insulin signaling promotes increased lifespan in a variety of model organisms. Increased glucose and insulin in the circulatory system will cause peripheral cells to absorb this glucose and convert it to ATP. In addition, insulin will also send positive growth and proliferative signals, pushing cellular balance toward growth and cell division. Therefore, CR may promote increased lifespan by decreasing rates of cell division and favoring repair and maintenance. The growth hormone-IGF-1 axis hypothesis states that increased signaling through these pathways advances the aging process by promoting cell growth and proliferation. Similarly to the glucose-insulin level hypothesis, CR causes the reduction of growth hormone/IGF-1 signaling, favoring a switch from cell growth and proliferation to maintenance and repair in mice. However, in human studies over a 2 year period of CR, no change in circulating IGF-1 levels were observed. These findings hint at two potential conclusions; (1) CR does not work in humans, only in mice, or (2) CR does not impact IGF-1 levels; however, it does impact other pathways, leading to at least increased healthspan, if not lifespan.

The hormesis hypothesis states that low levels or intensity of stress leads to "priming" in which cells/tissues/organs can then withstand other stresses that would normally prove terminal. It is thought that with hormesis, cells move from active growth and proliferation to a state that favors repair and maintenance. CR may prime cells by activating stress pathways to deal with later assault such as DNA damage. Other specific observations appear to favor this model, activating transcription factors and mechanisms controlling gene expression leading to increased levels of proteins mediating cellular stress responses. A large number of gene expression studies have been performed in order to determine the impact of CR on genome function. CR is well known to elicit a change in cell behavior marked by a decrease in cell proliferation and shift to cellular maintenance and repair. Changes in phenotype are accompanied by changes in gene expression; therefore, what impact does CR have on gene expression from across the genome?

It is clear that CR results in decreased energy and changes in cellular AMP:ATP and NAD:NADH ratios. Compounds that mimic CR do so by impacting cellular function resulting energy readouts or interfering with signaling down-stream cellular energy levels. The main proteins that appear central to mediating this response are AMPK and SIRT1 which regulate cycles of deacetylation and phosphorylation of a large number of proteins to control gene expression and cellular functions. Many of the CR mimetics of naturally occurring compounds identified either modulate SIRT1/AMPK function or, for example with rapamycin, target downstream signaling hubs to mediate potential health and lifespan effects. Of these targets NF-κB and the FOXO family of transcription factors, are pivotal in promoting decreased cell proliferation and increased maintenance in normal cells, while facilitating apoptosis and cell death in cancer cells. Furthermore, although all compounds appear to confer life and healthspan extending impacts across numerous cell types and model organisms via this SIRT1/AMPK interaction, the downstream impact on genome function (gene expression) is varied, across cell-type, organism-type, and compound-type in addition to variations in experimental details (such as exposure times, drug concentrations). This suggests that although mechanisms mediating health and lifespan in response to CR and these compounds are similar, the effects on gene expression mean that these compounds may not be direct mimetics of CR or of one another.

Calorie Restriction and Protection Against Age-Related Neurological Disorders

The practice of calorie restriction is demonstrated to slow near every aspect of aging in laboratory species, and in humans it greatly improves measures of health related to risk of age-related disease. Here researchers look specifically at effects on the molecular biochemistry of cells in the brain, protective mechanisms that slow the progression and impact of age-related neurological disorders:

Mechanisms that increase longevity and, perhaps most importantly, promote longer health spans (lower or delayed incidence of age-related diseases) have always attracted attention. The most effective intervention known to date to prevent age-related decline and promote better health spans in a wide variety of organisms, ranging from yeast to primates, is caloric restriction (CR). This dietary intervention typically consists of a 20-40% reduction in caloric intake without micronutrient limitation relative to an ad libitum diet. Perhaps the most striking group of age-related diseases prevented by CR is in the brain. A large number of neurological disorders are age-related, and CR has been demonstrated to effectively prevent these disorders. CR also improves age-related declines in memory and learning abilities observed in elderly animals. Although the mechanisms by which CR exerts its effects are poorly understood, mitochondria, as master regulators of cellular metabolism, are believed to play an important role in the cellular adaptations that take place with the diet.

In the brain, increases in mitochondrial activity may change the susceptibility to excitotoxicity, a pathological process associated with many age-related neurological conditions such as stroke, Alzheimer's disease and Parkinson's disease, in which excessive activation of postsynaptic receptors results in cell death. This neurodegenerative process involves the binding of glutamate or glutamate analogues to NMDA and AMPA receptors, resulting in pathological increases in cytosolic calcium levels and a rapid decrease in ATP levels due to the activation of ionic balance restoration pathways. Mitochondria are the main site for ATP production in neurons and contribute toward cellular calcium buffering by accumulating this ion in a membrane potential-dependent manner. Indeed, interventions that increase mitochondrial calcium buffering capacity protect against excitotoxicity and related conditions. Interestingly, while intermittent fasting (a dietary intervention that consists in offering food ad libitum on alternate days) has been found to be neuroprotective under excitotoxic conditions, the effects of CR on excitotoxicity have not been well explored to date. Furthermore, mechanistic insights toward possible neuroprotective effects of this diet are still scarce. The aim of this study was to determine the effects of CR on excitotoxicity and dissect the molecular mechanisms involved.

We show that CR is also effective in preventing direct excitotoxic damage. Our data show that mitochondria in the brains of CR animals have enhanced electron transport capacity, accompanied by higher levels of some electron transport proteins and proteins involved in mitochondrial morphology and dynamics. Interestingly, the increase in electron transport chain (ETC) enzyme activities does not seem to affect the respiratory rates of isolated mitochondria. Cells seem to be able to regulate independently many different mitochondrial features. In our case, CR increases the levels of cardiolipin in the brain, while the activity of citrate synthase remains constant. Moreover, some, but not all, mitochondrial proteins are enriched in a per mitochondrion basis after CR. Some of the metabolic adaptations that CR induces in the brain seem to be mediated by molecule(s) present in the bloodstream. Indeed, CR serum promotes mitochondrial adaptations in primary neurons analogous those observed in vivo, namely protection against glutamate excitotoxicity. Previous reports in other tissues indicate that metabolic effects observed with CR can be partly reproduced in vitro using serum from animals subjected to the diet. These results support the notion that the metabolic remodeling that takes place with CR can be triggered by circulating molecules. A possible candidate is adiponectin, which is elevated in CR animals. Adiponectin protects against excitotoxicity both in vivo and in vitro.

Our results in brain mitochondria show that CR promotes sizable increases in both the rate and the accumulation capacity for calcium. As a result, under excitotoxic conditions, CR neurons possess a largely enhanced ability to buffer cytosolic calcium levels, which explains the strong resistance toward excitotoxic damage conferred by this dietary intervention both in vitro and in vivo. Overall, we demonstrate that CR is a highly effective intervention to prevent excitotoxic neuronal cell death by enhancing antioxidant capacity, mitochondrial respiratory rates, preventing mitochondrial permeability transition and thus enhancing calcium accumulation capacity, resulting in lower cell death. These properties may be central to the mechanism through which this dietary intervention promotes its many beneficial neurological effects.

ERK Inhibition Proposed as a Target for Muscle Regeneration

Many researchers are investigating potential means to spur greater muscle growth and regeneration in older people, ways to at least partially compensate for the characteristic loss of muscle mass and strength that occurs with age, a condition known as sarcopenia. Physical weakness is a sizable component of the frailty of aging, and restoring the ability of the elderly to move and act with confidence would be a tremendous gain. The current range of candidate therapies tend not to address root causes, the underlying molecular damage that causes aging, and vary from the debatable amino acid supplementation to the very promising myostatin blockade. Here researchers propose another possible target and present initial results in mice:

Sarcopenia, age-related loss of muscle quantity and quality, is a crucial determinant of geriatric fragility. Sarcopenia increases susceptibility to muscle damage, serious falls, obesity and diabetes. Age-related changes in muscle are thought to depend on a decrease in muscle stem cells and their niche, which results in global changes in associated gene and protein expression as well as posttranslational modifications. Skeletal muscle regeneration is a multistep process. In response to stimuli generated by exercise or injury, satellite cells re-enter the cell cycle to produce myoblasts, subsequently withdraw from the cell cycle, and differentiate into myocytes, which fuse into new myotubes or with host myofibers. This fusion process is crucial for postnatal growth, maintenance and repair of skeletal muscle in the adult stage. Myotube formation is completely Ca2+ dependent, and requires net Ca2+ influx into myoblasts.

With aging, skeletal muscle shows impaired myogenic potential, which, in turn, induces atrophy. Ca2+ signaling molecules are reported to be associated with age-dependent muscle degeneration. Among the various Ca2+ sensors and channels, inositol 1,4,5-triphosphate receptor type 1 (ITPR1) expression was dramatically decreased in aged muscles and myoblasts. Here, we have provided new evidence that decreased expression of ITPR1 triggers dysregulation of Ca2+ oscillation, which in turn modulate gene expression, resulting in defective myogenesis. Ca2+ oscillation is known to modulate gene expression in many tissues, including muscle.

Multiple studies suggest an important role for the Ras-ERK1/2 pathway in the development, maintenance, and pathology of mammalian skeletal muscle. ERK activity promotes the proliferation of myoblasts and the terminal differentiation of myotubes. We further investigated whether EGFR-Ras-ERK signaling is activated in aged skeletal muscle with decreased ITPR1 expression. Notably, the age-related ITPR1 decline in mice and human skeletal muscles was correlated with increased activation of EGFR-Ras-ERK signaling. To establish whether ERK activation is responsible for inhibition of myogenesis, the ERK pathway was blocked with a specific inhibitor, U0126, in old primary myoblasts. To further evaluate the therapeutic potential of ERK signaling inhibitors for sarcopenia, we examined the effects of U0126 on impaired muscle regeneration in aged mice. U0126 was injected on a daily basis into 6 and 24 month-old C57BL/6 male mice for 13 days after injury. Quantitative real-time PCR data revealed that U0126 induced higher expression of not only myogenic regulatory genes but also those involved in hypertrophy in aged muscle. Consistently, measurements revealed that the newly formed myofibers of U0126-treated muscle had significantly larger diameters than those of controls, supporting the potential of ERK inhibitors as new candidate therapeutic agents for sarcopenia.

Visceral Fat Harms Cardiovascular Health and Increases Risk of Disease

Visceral fat is the fat tissue packed around the abdominal organs, as opposed to the more visible subcutaneous fat under the skin. It is much more harmful and metabolically active. The more visceral fat tissue you have, and the longer you carry it, the shorter your life expectancy, the higher your lifetime medical costs, and the greater your risk of suffering all of the common age-related diseases. At present the research community consensus is that chronic inflammation is the major mechanism connecting these items; visceral fat tissue acts to increase inflammation through a number of processes, and inflammation is a major contributing factor to the pace at which age-related disease and dysfunction emerges.

Studies have shown that people who carry excess abdominal fat around their midsection tend to face higher risks of heart disease compared to people who have fat elsewhere. A new study adds to the growing body of evidence that regional fat deposits are harmful and further suggests that the density of the stomach fat (measured by CT scan) is just as important as how much fat you have. In general, the higher the fat content, the lower the attenuation, or fat density, that is shown on the CT image. "What's really interesting is that we show that an increase in the amount of stomach fat and a lower density fat is associated with worse heart disease risk factors - even after accounting for how much weight was gained. This hasn't been shown before. Measuring fat density is a new measure that we are still working to understand and warrants further investigation. We used it as an indirect measure of fat quality and found that lower numbers were linked to greater heart disease risk."

Researchers sought to determine whether there was a link between anatomical changes in belly fat - both its volume (quantity) and density - and changes in a broad array of cardiovascular disease risk factors during the average six-year study period. They reviewed CT scans to assess how much abdominal fat had accumulated, its location and it's density in 1,106 participants from the Framingham Heart Study who received this imaging as part of a larger study to measure coronary and abdominal aortic calcification. Participants' average age was 45 years and 44 percent were women. Both subcutaneous adipose fat, the fat just under the skin, and visceral adipose fat, the fat inside the abdominal cavity, were measured. Over the six-year follow-up period, participants had a 22 percent increase in fat just under the skin and a 45 percent increase in fat inside the abdominal cavity on average. In general, increases in the amount of fat and decreases in fat density were correlated with adverse changes in heart disease risk. Each additional pound of fat from baseline to follow up was associated with new onset high blood pressure, high triglycerides and metabolic syndrome. Even though increases in both types of fat were linked to new and worsening cardiovascular disease risk factors, the relationship was even more pronounced for fat inside the abdominal cavity compared to fat just under the skin.

Overall, associations remained significant even after adjusting for changes in BMI or waist circumference. Researchers also grouped participants into three groups according to abdominal adipose tissue volume and density change; they found that those with greater increases in fat volume and more decreases in fat density had relatively higher incidence of heart disease risk factors. In terms of next steps, more work needs to be done to understand fat density, and why and how it is associated with metabolic consequences of obesity (e.g., hypertension, abnormal cholesterol, diabetes, inflammation and insulin resistance). As well, it will be important to tease apart how less dense fat, along with simultaneous increases in the amount of fat may spur the development of harmful cardiometabolic changes.

Speeding up Drug Discovery for Geroprotectors

I'm far from convinced it is the best path forward in the matter of treating aging, but much of the research community is focused on finding drugs that can alter patterns of gene expression and the operation of signaling pathways that tend to change with aging in order to run in a more youthful manner. There are hundreds of potential candidates at this point, described in the geroprotectors database; things like metformin and rapamycin are in that list. This seems to me to be putting the cart before the horse, in that these changes are not the cause of aging but rather downstream consequences of cell and tissue damage. It is possible that some benefit can be obtained by forcing a more youthful function of cells despite the underlying damage that they are reacting to, but trying to coax a damaged machine into better function without actually repairing that damage tends to be an expensive exercise in obtaining only marginal results. Most of the medicine for age-related disease created over the past century establishes the bounds of the possible here, as next to none of it touches on the root causes of aging. You can slow things down, or make things somewhat better, but you can't produce the large improvements that would be possible by reverting the damage that causes aging. Is that worth the effort now, at a time when addressing the root causes of aging is actually plausible? I'd say no. Pursue the better strategy instead, that outlined by the SENS rejuvenation research program, a focus on repair of fundamental damage rather than trying to compensate for it.

A significant rise in the proportion of seniors worldwide is underway, resulting in increasing rates of chronic, debilitating disease and long term residential care, shrinking the supporting workforce, and threatening to sink current health care systems. Prevention will be crucial moving forward. If aging can be delayed and diseases prevented, productive years can be extended and retirement age redefined. Anti-aging therapies have been sought since the dawn of human civilization, but with the rise of modern biology, big data, and information sciences, intelligent approaches to geroprotector discovery may finally be within reach. The outward features of aging, including decline in function and rise in susceptibility to stress and disease, are associated with a set of structural and functional changes at the cellular level. While these changes vary by tissue, many are genetically regulated, and many genes mediating longevity, termed gerontogenes, have been identified. The identification of these genes and experimental manipulation of their products to extend lifespan in model organisms has bolstered the notion that aging is not just a natural process but a treatable disease and added credence to the movement to identify drugs or other factors that may also extend lifespan, or, more favorably, healthspan, in humans. These are termed geroprotectors.

There are now over 200 substances that have shown geroprotective effects in model organisms. Human-based studies, however, may turn out to be more productive. Several of the most promising attempts at developing geroprotectors have involved identifying FDA-approved drugs with life-extending qualities and repurposing them as geroprotectors for human use. These include rapamycin and metformin. However, a number of problems still hamper the widespread approval and use of these or other drugs for this purpose. Most notably, longevity is a difficult parameter to study in humans without large, longitudinal designs, and since these drugs would presumably be administered to aging but otherwise healthy individuals, the effect size would have to be substantial and side effects almost non-existent. In addition, the FDA does not consider aging an approved disease indication. At this time, no drug has sufficiently met these conditions, and new approaches to drug discovery - and drug repurposing - are needed.

The drug discovery process is slow and expensive, burdened by many projects that dead-end before clinical trial or fail thereafter. Improved prediction of drug performance prior to lengthy experimentation would cut waste. Vast datasets now exist that enable such prediction with the help of sophisticated computational methods. Two particularly valuable datasets in this respect are the literally millions of gene expression profiles stored in repositories and a number of increasingly diverse compound screening libraries. While gene expression data can be used to pinpoint target pathways for a particular disease, compound libraries can be screened for drugs that target these pathways. All of this can be done in silico, at relatively little cost. Recently, a method was developed that would do just this - capitalize on existing gene expression data and compound libraries to improve prediction of targeted drugs. The method involves the use of an algorithm termed Oncofinder. Oncofinder quantifies Pathway Activation Strength (PAS) in a given sample based on gene expression patterns relative to another sample. Thus PAS values can be computed for a disease state in comparison to a normal state, old versus young, or any other set of physiological conditions. Here, we used an aging-based extension of Oncofinder, known as GeroScope, in a search for novel geroprotective substances.

We first quantified activation of age-related pathways in hematopoietic and mesenchymal stem cells from "old" (vs "young") human donors. We then shortlisted substances predicted to best target those pathways, restore a "young" cellular profile, and extend viability. From that list, we proceeded to experimentally test the effects of each substance in human fibroblasts. The top geroprotector, in terms of performance in both enhancing viability and rejuvenation was PD-98059, a highly selective inhibitor of MEK1 and the MAP kinase cascade. MEK inhibition along with PI-3K inhibition has been shown to decelerate cellular senescence via the mTOR/S6 pathway, a known target for anti-aging interventions. Aside from PD-98059, most of the studied geroprotectors had effects on either cellular viability or senescence features.

Assessing the Brains of Supercentenarians

Supercentenarians, people who have passed 110 years of age, are very rare. Accordingly, the sort of information on their physiology that can only be obtained through autopsy or donation of the body to science is similarly thin on the ground. It has been some years now, for example, since the evidence was first gathered to show that most supercentenarians are probably killed by transthyretin amyloidosis, something that has a smaller but significant contribution to heart disease in earlier old age. Here, researchers assess the postmortem state of the brains of four supercentenarians, an exercise that well demonstrates that the oldest of humans don't escape unscathed:

Supercentenarians (aged 110 years old or more) are extremely rare in the world population (the number of living supercentenarians is estimated as 47 in the world), and details about their neuropathological information are limited. Based on previous studies, centenarians (aged 100-109 years old) exhibit several types of neuropathological changes, such as Alzheimer's disease and Lewy body disease pathology, primary age-related tauopathy, TDP-43 pathology, and hippocampal sclerosis. In the present study, we provide results from neuropathological analyses of four supercentenarian autopsy cases using conventional and immunohistochemical analysis for neurodegenerative disorders. In particular, we focused on the pathology of Alzheimer's disease and Lewy body disease, as well as the status of hippocampal sclerosis, TDP-43 pathology, aging-related tau astrogliopathy, and cerebrovascular diseases.

Three cases were characterized as an "intermediate" level of Alzheimer's disease changes (NIA-AA guideline) and one was characterized as primary age-related tauopathy. TDP-43 deposits were present in the hippocampus in two cases. Neither Lewy body pathology nor hippocampal sclerosis was observed. Aging-related tau astrogliopathy was consistently observed, particularly in the basal forebrain. Small vessel diseases were also present, but they were relatively mild for cerebral amyloid-beta angiopathy and arteriolosclerosis. Although our study involved a small number of cases, the results provide a better understanding about human longevity. Neuropathological alterations associated with aging were mild to moderate in the supercentenarian brain, suggesting that these individuals might have some neuroprotective factors against aging. Future prospective studies and extensive molecular analyses are needed to determine the mechanisms of human longevity.

Epigenetic Clock Data from a Larger Study Population

There are presently a few different biomarkers of aging under development based on changes in patterns of DNA methylation, an epigenetic decoration to DNA that determines the rate at which specific proteins are manufactured. The molecular damage that causes aging is the same in all of us, and thus some portion of the cellular reaction to environment and circumstances will also be the same in all of us: as damage accumulates, cells change their behavior in response. A good biomarker that accurately reflects biological age can, once validated, be used to greatly speed up development of therapies that slow or repair the causes of aging. At present the only reliable way to assess outcomes is to run life span studies, something that is for many organizations prohibitively expensive when carried out in mice, and out of the question when it comes to gathering human data. If lengthy life span studies can be replaced with a biomarker measurement before and after a short period of treatment, then the cost and time taken to evaluate potential rejuvenation therapies will be greatly reduced, and many more research groups will participate in the research and development process.

A team of 65 scientists in seven countries recorded age-related changes to human DNA, calculated the biological age of blood and estimated a person's lifespan. A higher biological age - regardless of chronological age - consistently predicted an earlier death. Drawing on 13 sets of data, including the landmark Framingham Heart Study and Women's Health Initiative, a consortium of 25 institutions analyzed the DNA in blood samples collected from more than 13,000 people in the United States and Europe. Applying a variety of molecular methods, including an epigenetic clock developed in 2013, the scientists measured the aging rates of each individual. The clock calculates the aging of blood and other tissues by tracking methylation, a natural process that chemically alters DNA over time. By comparing chronological age to the blood's biological age, the scientists used the clock to predict each person's life expectancy.

"Our findings show that the epigenetic clock was able to predict the lifespans of Caucasians, Hispanics and African-Americans in these cohorts, even after adjusting for traditional risk factors like age, gender, smoking, body-mass index and disease history. We discovered that 5 percent of the population ages at a faster biological rate, resulting in a shorter life expectancy. Accelerated aging increases these adults' risk of death by 50 percent at any age." For example, two 60-year-old men both smoke to deal with high stress. The first man's epigenetic aging rate ranks in the top 5 percent, while the second's aging rate is average. The likelihood of the first man dying within the next 10 years is 75 percent compared to 60 percent for the second. The preliminary finding may explain why some individuals die young - even when they follow a nutritious diet, exercise regularly, drink in moderation and don't smoke. "While a healthful lifestyle may help extend life expectancy, our innate aging process prevents us from cheating death forever. Yet risk factors like smoking, diabetes and high blood pressure still predict mortality more strongly than one's epigenetic aging rate."

The precise role of epigenetic changes in aging and death, however, remains unknown. "Do the epigenetic changes associated with chronological aging directly cause death in older people? Perhaps they merely enhance the development of certain diseases - or cripple one's ability to resist the progression of disease after it has taken root. Future research is needed to address these questions." Larger studies focused only on cases with well-documented causes of death will help scientists tease out the relationship between epigenetic age and specific diseases. "We must find interventions that prolong healthy living by five to 20 years. We don't have time, however, to follow a person for decades to test whether a new drug works. The epigenetic clock would allow scientists to quickly evaluate the effect of anti-aging therapies in only three years."

Ten Years of Induced Pluripotency

It has been a decade since researchers first discovered the recipe for reprogramming ordinary somatic cells into induced pluripotent stem cells, capable of generating all other cell types in the same way as embryonic stem cells. This was a transformative advance, as the ease of the method allowed near any research group to work with pluripotent cells. Making use of induced pluripotency in research and medicine is still very much a work in progress, however: great strides are being made in the production of cells and tissues for drug testing and other tissue engineering for research use, but the goals of generating patient-matched cells and tissues for cell therapies and transplantation are not proceeding as smoothly as was perhaps hoped by some. This popular science article surveys the field:

Human cortex grown in a petri dish. Eye diseases treated with retinal cells derived from a patient's own skin cells. New drugs tested on human cells instead of animal models. Research and emerging treatments with stem cells today can be traced to a startling discovery 10 years ago when researchers reported a way to reprogram adult mouse cells and coax them back to their embryonic state - pluripotent stem cells. A year later, they accomplished the feat with human cells. The breakthrough provides a limitless supply of induced pluripotent stem cells (iPSCs) that can then be directed down any developmental path to generate specific types of adult cells, from skin to heart to neuron, for use in basic research, drug discovery and treating disease. The dazzling iPSC breakthrough has spurred rapid progress in some areas and posed major challenges in others. It has already proved a boon to basic research, but applying the new technology to treat diseases remains daunting. Some types of cells have proved difficult to reprogram, and even the protocols for doing so are still in flux as this is still a very young field.

Six years after the iPSCs discovery, researchers in a very different field developed a new gene-editing technology of unprecedented speed and precision, known as CRISPR-Cas9. The potent new tool has revolutionized efforts to "cut and paste" genes and has been very quickly adopted by thousands of researchers in basic biology and drug development. CRISPR's speed and precision may some day allow stem cell researchers to reach their most ambitious goal: Genetically abnormal cells from patients with inherited diseases such as sickle cell anemia or Huntington's could be reprogrammed to the pluripotent stem cell state; their genetic defects could be "edited" in a petri dish before being differentiated into healthy adult cells. These cells could then be transplanted into patients to restore normal function. While that goal is still beyond reach, many early-stage clinical trials are underway using induced iPSCs to treat diseases, from diabetes and heart disease to Parkinson's. One trial has already treated its first patient. In 2014, scientists made iPSCs from skin cells of a woman with macular degeneration and then differentiated them into adult retinal cells. Surgeons transplanted the retinal cells into her eyes in order to treat the disease - the first patient treated using iPSCs. Preparations to treat a second patient using patient-derived cells were stopped because the researchers detected a mutation in one of the genes in the iPS cells. No reports had linked the gene to cancer, but they decided not to use the stem cells to eliminate any risk.

The success of treatments relies in part on stem cells' rapid rate of proliferation. Hundreds of billions of cells may sometimes be needed for a transplantation. But if just a few of the stem cells fail to differentiate into the target adult cells, they may reproduce rampantly when transplanted and form a tumor. "It's a two-edged sword. In the pre-transplant stage, you want stem cells that proliferate very rapidly. But after the transplant, if there are only five or 10 cells that didn't differentiate into adult cells, they can reproduce infinitely. They create a kind of residue of tumor." Research to ensure that all stem cells differentiate before transplantation is now one of the main issues in this field. To eliminate cancer risk, the researchers are now "deep sequencing" the genetic makeup of each of the stem cell lines they might use. They have also decided to use donor cell lines rather than the patient's own cells. This avoids the very expensive prospect of having to carry out quality checks like deep sequencing of each patient's own pluripotent cell lines.

The originators of the iPSC methodology are concerned about public perception that the rate of progress may be slower than expected. "I am fascinated by how rapidly science is advancing. It's amazing. But for the most part, developing new treatments - doing the science, testing the safety and effectiveness of new therapies­ - takes a great deal of money and many years. Developing new treatments may take 10 years, 20 years, 30 years. That is what we have been trying to say to our patients: 'We are making great progress, so do keep up your hope. But it takes time.'"

No Correlation of Telomere Length with Longevity in Nematodes

Average telomere length in cells reflects some combination of cell division rates and cell replacement rates: telomeres shorten with each cell division until cells self-destruct because telomeres are too short, and replacements are generated with long telomeres by stem cells. The stem cell activity that delivers those replacements tends to decline with age, and so average telomere length tends to decrease as well. But this is highly variable between individuals and with circumstances such as illness, exercise, and so forth. Researchers only see the decline in statistics gathered across a large study population, making this a terrible measure of aging for any individual consideration. Added to this, for every paper to show some useful correlation for telomere length, there is another to show no useful correlation between teleomere length and measures of aging, such as this one that examines natural variations in telomere length and longevity in nematode worms:

Telomeres are involved in the maintenance of chromosomes and the prevention of genome instability. Despite this central importance, significant variation in telomere length has been observed in a variety of organisms. The genetic determinants of telomere-length variation and their effects on organismal fitness are largely unexplored. Here, we describe natural variation in telomere length across the Caenorhabditis elegans species. We identify a large-effect variant that contributes to differences in telomere length. The variant alters the conserved oligonucleotide/oligosaccharide-binding fold of protection of telomeres 2 (POT-2), a homolog of a human telomere-capping shelterin complex subunit. Mutations within this domain likely reduce the ability of POT-2 to bind telomeric DNA, thereby increasing telomere length.

Our observation that considerable telomere-length variation in the wild isolate population exists allowed us to directly test whether variation in telomere length contributes to organismal fitness. We did not see any correlation between telomere length and offspring production, suggesting that fitness in wild strains is not related to telomere length. In contrast to findings in human studies, we did not identify a relationship between telomere length and longevity. Our results confirm past findings that telomere length is not associated with longevity in a small number of C. elegans wild isolates or laboratory mutants. In summary, this study demonstrates that a variant in pot-2 likely contributes to phenotypic differences in telomere length among wild isolates of C. elegans. The absence of evidence for selection on the alternative alleles at the pot-2 locus and the lack of strong effects on organismal fitness traits suggest that differences in telomere length do not substantially affect individuals at least under laboratory growth conditions.

Alternate Day Fasting Slows Progression of Glaucoma in an Animal Model

Calorie restriction is here demonstrated to slow the progression of glaucoma in a mouse model of the condition, without affecting the rising pressure inside the eye that is usually the cause of harm. It is an interesting demonstration of the way in which the shifts in cellular metabolism that occur with calorie restriction prime cells to be more resistant to a range of stresses that typically cause significant amounts of cell death:

Glaucoma is characterized by progressive degeneration of retinal ganglion cells (RGCs) and their axons. We previously reported that loss of glutamate transporters (EAAC1 or GLAST) in mice leads to RGC degeneration that is similar to normal tension glaucoma and these animal models are useful in examining potential therapeutic strategies. Caloric restriction has been reported to increase longevity and has potential benefits in injury and disease. Here we investigated the effects of every-other-day fasting (EODF), a form of caloric restriction, on glaucomatous pathology in EAAC1-/- mice.

EODF suppressed RGC death and retinal degeneration without altering intraocular pressure. Moreover, visual impairment was ameliorated with EODF, indicating the functional significance of the neuroprotective effect of EODF. Several mechanisms associated with this neuroprotection were explored. We found that EODF upregulated blood β-hydroxybutyrate levels and increased histone acetylation in the retina. Furthermore, it elevated retinal mRNA expression levels of neurotrophic factors and catalase, whereas it decreased oxidative stress levels in the retina. Our findings suggest that EODF, a safe, non-invasive, and low-cost treatment, may be available for glaucoma therapy.


Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.