Fight Aging!

Below you'll find links to open access reviews on the current state of two different areas of applied stem cell science: reversing muscle loss in aging and degenerative conditions, and repairing forms of blindness caused by retinal degeneration. Consider these representative of many other similar efforts, as for near every part of the body there are teams out there somewhere working on how to apply stem cells to reverse damage and restore function. It is a very broad, active, and well-funded field of research, all told.

Retinal Stem Cells and Regeneration of Vision System

Eye formation requires the coordination of complex interactions from multiple cellular sources to create the cell behaviors that progressively shape the developing eye. The mechanisms of development and differentiation of eye are remarkably similar in all vertebrates. During retinogenesis, proliferating retinal pigment cells (RPCs) and newly generated cells are confined at the peripheral margin of the retina. In fish and amphibians, this region is maintained after embryonic development and this specialized region referred to as the CMZ. The retina of many fish and amphibians continue to grow throughout their life. The increase in retinal size is due to in part to the addition of new neurons, at the CMZ. In birds, neurogenesis at the CMZ decreases dramatically than that observed in fish and amphibians. Furthermore, in rodents the retinal margin does not exhibit mitotic activities after the first week of postnatal life. It is interesting to note that there might be a direct correlation of the evolutionary importance of the ability of retina to regenerate with the presence of RPCs and their potential to generate retinal neurons.

Adult mammalian retina has long been known to be devoid of stem cells and has lost the ability to regenerate after damage. Nevertheless, several groups have reported that pigmented cells isolated from the adult human ciliary epithelium can transdifferentiate to retinal progenitor-like cells and Müller glia cells can display characteristics of neural progenitor cells, thus identified both cell populations as potential candidate for stem-cell based therapies to regenerate visual function.

It seems logical that it is preferable to mobilize endogenous RPCs to drive the repair process in the retina. However, the challenge of using endogenous RPCs for self repair will be to identify appropriate cellular sources and molecules, including pharmacological agents, that can expand the endogenous cell pool and reactivate the regenerative processes similar to those described for the lower vertebrates in the mammalian retina.

Recent advances in stem cell research have raised the possibility to use human embryonic stem cells and induced pluripotent stem cells to repair or regenerate damaged mammalian retina. Cell transplantation is the most direct approach towards replacing damaged retinal cells and restoration of lost visual function. To achieve a breakthrough in cell replacement therapies in retinal degenerative diseases would require isolation and molecular characterization of human RPCs for specific neuronal replacement in the actively degenerating adult retina and that these new cells survive without immune suppression as well as displaying evidence of integration into host circuitry.

Advancements in stem cells treatment of skeletal muscle wasting

Muscular dystrophies (MDs) are a heterogeneous group of inherited disorders, in which progressive muscle wasting and weakness is often associated with exhaustion of muscle regeneration potential. Although physiological properties of skeletal muscle tissue are now well known, no treatments are effective for these diseases. Muscle regeneration was attempted by means of transplantation of myogenic cells (from myoblast to embryonic stem cells) and also by interfering with the malignant processes that originate in pathological tissues, such as uncontrolled fibrosis and inflammation. Taking into account the advances in the isolation of new subpopulation of stem cells and in the creation of artificial stem cell niches, we discuss how these emerging technologies offer great promises for therapeutic approaches to muscle diseases and muscle wasting associated with aging.

New approaches using organisms genetically modified and transgenic mouse models proposed the importance of the microenvironment - like the niche and the extrinsic factors - to be a key component in stem cell regulation. Particularly, significant progress has been made in understanding how satellite cells can act as tissue-specific adult stem cells in skeletal muscle. In the same time, many studies investigated the satellite cell properties in term of efficacy after in vivo transplantation using novel approaches such as non-invasive bioluminescence imaging. These tools provided information for assessing not only satellite cell function but, in general, stem cell function. Investigations on the molecular nature of stem cell niche signals on in vivo models and short-term cultures of isolated myofibers, are now on-going.

Bioengineering offers significant tools for the development of strategies to mimic biochemical and biophysical features of the in vivo niche microenvironment. We hope that the synthesis of biomaterials, micro-fabrication technology and stem cell biology will provide systems potentially innovative to better understand how stem cell fate is controlled. Development of biomaterials able to re-create an in vitro stem cell niche could give rise to novel insights into understanding the molecular cues, critical for the in vitro maintenance and expansion of muscle stem cells. Above all, these in vitro systems can well lead to the generation of adequate numbers of stem cells and the ability to control their differentiation in order to maximize their utility, not only as cell-based therapeutics for tissue regeneration and replacement, but also as the control of inflammation after muscle damage.

There is some debate over whether rapamycin administration actually slows aging or only reduces cancer risk in mice: both sides argue the point from rigorous studies, but unlike many other compounds and methodologies the evidence for life extension in mice is strong and reproducible. These are debates over the cause of that life extension.

The recent paper quoted below comes from researchers who favor manipulation of mTOR as a way forward to treat aging, and who argue that rapamycin does slow aging. But again, from my point of view all such efforts to develop drugs to alter metabolism to modestly extend life are the slow, expensive road to a poor end result. We should be focused on building therapies to repair the damage that causes aging, an end result that is both of greater utility and can meaningfully help old people. There is not much use in a way to slow aging when you are already old.

Target of Rapamycin (TOR) is involved in cellular and organismal aging. Rapamycin extends lifespan and delays cancer in mice. It is important to determine the minimum effective dose and frequency of its administration that still extends lifespan and prevents cancer. Previously we tested 1.5 mg/kg of rapamycin given subcutaneously 6 times per two weeks followed by a two-week break. This intermittent treatment prolonged lifespan and delayed cancer in cancer-prone female FVB/N HER-2/neu mice.

Here, the dose was decreased from 1.5 mg/kg to 0.45 mg/kg per injection. This treatment was started at the age of 2 months (group Rap-2), 4 months (Rap-4), and 5 months (Rap-5). Three control groups received the solvent from the same ages. Rapamycin significantly delayed cancer and decreased tumor burden in Rap-2 and Rap-5 groups, increased mean lifespan in Rap-4 and Rap-5 groups, and increased maximal lifespan in Rap-2 and Rap-5 groups. In Rap-4 group, mean lifespan extension was achieved without significant cancer prevention.

The complex relationship between life-extension and cancer-prevention depends on both the direct effect of rapamycin on cancer cells and its anti-aging effect on the organism, which in turn prevents cancer indirectly. We conclude that total doses of rapamycin that are an order of magnitude lower than standard total doses can detectably extend life span in cancer-prone mice.

Link: https://www.landesbioscience.com/article/28164/full_text/#load/info/all

The history of results achieved while trying to extend mouse life span via manipulation of sirtuins with drugs is not particularly impressive, all told, characterized by an inability to replicate early results, a lack of effectiveness, and challenges from the rest of the scientific community. Nonetheless sirtuins play a role in numerous cellular mechanisms of general interest, so research continues in that sense.

Here one of the later drug candidates for sirtuin manipulation is claimed to modestly extend mean mouse life span - but based on the history you should probably not be terribly excited by this news, even if you consider the development of drugs to slow aging by metabolic manipulation to be a useful activity rather than a distraction from better forms of longevity science:

The prevention or delay of the onset of age-related diseases prolongs survival and improves quality of life while reducing the burden on the health care system. Activation of sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, improves metabolism and confers protection against physiological and cognitive disturbances in old age. SRT1720 is a specific SIRT1 activator that has health and lifespan benefits in adult mice fed a high-fat diet.

We found extension in lifespan, delayed onset of age-related metabolic diseases, and improved general health in mice fed a standard diet after SRT1720 supplementation. Inhibition of proinflammatory gene expression in both liver and muscle of SRT1720-treated animals was noted. SRT1720 lowered the phosphorylation of NF-κB pathway regulators in vitro only when SIRT1 was functionally present. Combined with our previous work, the current study further supports the beneficial effects of SRT1720 on health across the lifespan in mice.

Link: http://www.cell.com/cell-reports/abstract/S2211-1247(14)00065-5?switch=standard

The Immortalists is a human interest film focused on Aubrey de Grey of the SENS Research Foundation and Bill Andrews of Sierra Sciences, and will premier at this year's SXSW.

Two extraordinary scientists struggle to create eternal youth with medical breakthroughs in a world they call "blind to the tragedy of old age." Bill Andrews is a lab biologist and famed long-distance runner racing against the ultimate clock. Aubrey de Grey is a genius theoretical biologist who conducts his research with a beer in hand. They differ in style and substance, but are united in their common crusade: cure aging or die trying. They publicly brawl with the old guard of biology who argue that curing aging is neither possible nor desirable. As they battle their own aging and suffer the losses of loved ones, their journeys toward life without end ultimately become personal.

As you might guess this isn't really a popular science effort, but rather an entry into the time-honored documentary genre of giving screen time to strong characters in an industry largely unfamiliar to the public, people who are forging their way against the flow, working to achieve great and unusual things. There's a blog and PDF press kit if you want to look further.

You can also get a sense of the thing from the trailer, but I'll use this as a springboard to note the existence of a very real challenge when it comes to advocacy and fundraising for efforts to develop the means to treat and reverse degenerative aging. The public at large, and even people who take a little time to investigate the work of the research community, largely cannot tell the difference between serious efforts that might actually work, such as the work of the SENS Research Foundation and its allies, and scientific-sounding efforts that are in fact just ways to sell supplements that cannot possibly do anything meaningful to the course of aging, which is what has become of Sierra Sciences.

Sierra Sciences was at one point a serious effort to investigate manipulation of telomeres and telomerase as a means to treat aging, but at some point venture capital demands profits. Hence the slide of this company, like others before it, from legitimate research venture to just another group selling packaged herb extracts. Somewhere back in the day someone figured out that if you sound like a scientist people will buy what you sell regardless of how dubious your pitch is. It works even better if you actually used to be a scientist - so that's what we tend to see in this sort of situation. It's a damn shame, but it is what it is.

So you have a film equating de Grey, who coordinates a well-supported disruption of the status quo in aging research, complete with ongoing research projects aimed at the creation of actual, real rejuvenation over the next few decades, with Andrews, who is a scientist turned supplement seller - yet another in the long series of people to leave the rails of doing meaningful research in favor of hawking marginal and frankly dubious products here and now. These two people and the broader efforts they represent couldn't be more different. One is a shot at rejuvenation, and the other has made himself irrelevant to that goal.

This is a microcosm of the reasons why much of the mainstream scientific community are exceedingly unhappy with the "anti-aging" marketplace. When folk in the street - and journalists who know better, but who live and die by page view counts - don't take the time to distinguish between fraudulent "anti-aging" products and legitimate laboratory research, and the largest megaphones are wielded by supplement sellers, then the fundraising environment for aging research becomes challenging.

The future of longevity is not herbal supplements, never was herbal supplements, and never will be herbal supplements. Anyone trying to sell you a supposedly longevity-enhancing ingested product here and now, today, has left the real road to human rejuvenation far behind. All they have to sell are wishes, dreams, and lies. The only valid, viable way forward is to fund the right sort of research: the development of targeted therapies capable of repairing or reversing the known root causes of aging, and stop-gap treatments such as stem cell therapies that can temporarily reverse some of the consequences of aging to a degree that merits the high cost of development. Nothing exists today that can accomplish that first goal, and it will be at least two decades before early rejuvenation therapies emerge, even assuming great progress in fundraising over that time.

So to meander to a conclusion: there is probably no such thing as bad publicity. The more that the public hears about the prospects for treating aging, more likely it is that some people will come to favor that goal, and the easier it becomes for scientists to raise funds for new ventures or to expand existing SENS programs. But I, not in the target audience of course, would much prefer to see that done in a more discriminating way than the example herein.

Cancer and Alzheimer's disease appear to be inversely related. If you have cancer your odds of Alzheimer's are lower, and vice versa. Since the lifestyle risk factors for both are essentially the same, this is an interesting finding, to say the least. Researchers are digging into the biochemical mechanisms that might explain this state of affairs:

There is epidemiological evidence that patients with certain Central Nervous System (CNS) disorders have a lower than expected probability of developing some types of Cancer. We tested here the hypothesis that this inverse comorbidity is driven by molecular processes common to CNS disorders and Cancers, and that are deregulated in opposite directions.

We conducted transcriptomic meta-analyses of three CNS disorders (Alzheimer's disease, Parkinson's disease and Schizophrenia) and three Cancer types (Lung, Prostate, Colorectal) previously described with inverse comorbidities. A significant overlap was observed between the genes upregulated in CNS disorders and downregulated in Cancers, as well as between the genes downregulated in CNS disorders and upregulated in Cancers. We also observed expression deregulations in opposite directions at the level of pathways.

Our analysis points to specific genes and pathways, the upregulation of which could increase the incidence of CNS disorders and simultaneously lower the risk of developing Cancer, while the downregulation of another set of genes and pathways could contribute to a decrease in the incidence of CNS disorders while increasing the Cancer risk. These results reinforce the previously proposed involvement of the PIN1 gene, Wnt and P53 pathways, and reveal potential new candidates, in particular related with protein degradation processes.

Link: http://dx.doi.org/10.1371/journal.pgen.1004173

Numerous studies now show that stem cell populations in old tissues remain large, and have explored a few of the mechanisms that explain why these stem cells are no longer as active in tissue maintenance as they were in youth. In a number of cases researchers have been able to demonstrate partial reversal of this decline by altering the signaling environment, overriding the age-related changes that seem to be responsible without addressing the underling causes of these changes, which are no doubt reactions to rising levels of cellular damage.

It is likely that researchers will find naive applications of this sort of restoration of stem cell activity will greatly raise cancer risk, as cancer suppression is probably the reason why stem cells have evolved this diminished action response to the damage of aging - our longevity is thought by many researchers to be a balancing act between risk of cancer and levels of tissue maintenance in an environment of steadily rising damage. The ability to detect and selectively and safely treat cancer is improving rapidly, however, so a blunt restoration of stem cell activity may well turn out to be an acceptable stop-gap approach to improve health in old age:

Previous studies have demonstrated an age related decline in the size of the neural stem cell (NSC) pool and a decrease in neural progenitor cell proliferation, however, the mechanisms underlying these changes are unclear. In contrast to previous reports, we report that the numbers of NSCs is unchanged in the old age subependyma and the apparent loss is because of reduced proliferative potential in the aged stem cell niche.

Transplantation studies reveal that the proliferation kinetics and migratory behavior of neural precursor cells are dependent on the age of the host animal and independent of the age of the donor cells suggesting that young and old age neural precursors are not intrinsically different. Factors from the young stem cell niche rescue the numbers of NSC colonies derived from old age subependyma and enhance progenitor cell proliferation in vivo in old age mice. Finally, we report a loss of Wnt signaling in the old age stem cell niche that underlies the lack of expansion of the NSC pool after stroke.

Link: http://dx.doi.org/10.1016/j.neurobiolaging.2014.01.026

It is a given that women tend to live longer than men, a difference that becomes ever more apparent as demographic cohorts approach extreme old age. Four of every five centenarians are women, for example. This disparity has long been noted, and yet, as is the case for many apparently simple questions about the biochemistry of aging, there are as yet no definitive, final answers as to why this situation exists, how it came about though natural selection, and what exactly determines gender differences in longevity at the level of metabolic processes and epigenetic patterns of gene expression. There are a great many theories, however. If you want to see scientific undergrowth at its thickest, tangled and disputed, look no further than this topic.

Any proposed comprehensive theory on gender longevity differences in humans should probably also touch on two oddities in our species: firstly that women live long past menopause, and secondly that we are very long-lived in comparison to other mammals of a similar size, including our closest relatives among the primates. The grandmother hypothesis is often put forward in connection with these points, but is by no means universally accepted: it is the idea that our intelligence, tool-use, and culture allow older post-reproductive individuals to increase the reproductive success of their direct descendants in ways that simply don't happen in other species.

Here is a very readable open access paper that walks through one researcher's assembly of a theory of human aging and its unusual aspects, touching on a range of research from recent years, some of which you might recall being mentioned here. As for many similar topics this has very little bearing on the pressing issue of building effective treatments for degenerative aging, but it is a part of the very interesting backdrop to that work: there is great complexity to aging, and the genius of the repair based approach of SENS and similar initiatives is the recognition that most of that complexity can be bypassed and ignored. We simply don't need to fully comprehend degenerative aging in order to remove it from the human condition.

Evolution of sexually dimorphic longevity in humans

The pattern of human aging exhibits a number of salient features that have long engaged evolutionary biologists. For one, among the higher primates, human being are unusually long lived. The maximum lifespans of orang-utans and gorillas are 58.7 and 54 years, respectively, and those of our closest relatives, bonobos and chimpanzees are 50 and 53.4 years, respectively. By contrast, maximum human lifespan varies from 85 in foraging groups such as the Aché in Paraguay and Kung bushmen, to 122 in the developed world. This implies that an evolutionary spurt of increased longevity must have occurred since the last common ancestor of humans and chimpanzees/bonobos walked the earth some 5-7 million years ago.

Another striking feature of human aging is its sexual inequality. As life expectancy has increased with improvements in living conditions during the last century, there has consistently emerged a survival difference between the sexes, with women living longer. For example, in the UK estimated life expectancies for women and men from birth (2012) are 82.4 and 78.0 years, respectively, a difference of 4.4 years. Some other examples of gender gaps are the USA 5.0 years (81.0F - 76.0M), France 6.4 years (84.7F - 78.3M) and Russia 13.0 years (73.1F - 60.1M). The gender gap reflects a greater susceptibility of men to a wide range of aging related pathologies, including cardiovascular disease, type II diabetes, infection and sarcopenia (aging-related loss of muscle mass). The basis of male frailty remains unclear, either in terms of its evolutionary origins or somatic causes.

The other gender gap in aging affects reproductive lifespan. Women's capacity reproduce is lost in their late 40s, as they undergo the menopause, while men can remain fertile at least into their early 80s. The significance of the early cessation of reproduction in women is a topic of much discussion, in particular, whether or not it is an adaptation and contributes to evolutionary fitness.

Why do humans live longer than other higher primates? Why do women live longer than men? What is the significance of the menopause? Answers to these questions may be sought by reference to the mechanisms by which human aging might have evolved. Here, an evolutionary hypothesis is presented that could answer all three questions.

It might be argued that the ability to generate data in the life sciences is presently somewhat ahead of innovation in ways to make that data useful. There is the sense, looking at just how much can be measured and the power of modern computing and analysis methodologies, that there must be more ways to extract useful predictions of the life-extending potential of various treatments.

The direction of much of modern medicine is to focus on the development of treatments that work by altering gene expression or otherwise manipulating levels of specific proteins. The process of finding targets is made more effective via analysis of the vast amounts of gene expression data that can be cheaply obtained from patients and healthy individuals nowadays. Relationships between proteins can be established and differences between healthy and unhealthy biology identified.

My objection to this approach taken as a whole is that it is essentially only a more efficient continuation of the same old take on applied medicine: to patch over the problem rather than address the underlying cause. It is adjusting the engine's fuel feed to force your way past the fact that critical components are worn and faulty. Some forms of adjustment in biology can produce overall benefits on the level of damage in the system: think of approaches that boost the operation of cellular housekeeping, for example. But that isn't the case for most of what comes out of this school of research and development.

Here is an example of applying this approach to aging - the paper is open access, but not yet available in plain text format, so note the provisional PDF link on the page if you want to dive in. I'd say that this is a great path ahead if you favor programmed aging theories, as in that worldview aging is caused by evolved changes in gene expression over time: reverse the changes and you reverse aging. If you hold of the majority view of aging as accumulated cellular and molecular damage, however, then all of what I said above applies.

The major challenges of aging research include absence of the comprehensive set of aging biomarkers, the time it takes to evaluate the effects of various interventions on longevity in humans and the difficulty extrapolating the results from model organisms to humans. To address these challenges we propose the in silico method for screening and ranking the possible geroprotectors followed by the high-throughput in vivo and in vitro validation.

The proposed method evaluates the changes in the signaling pathway cloud constructed using the gene expression data and epigenetic profiles of young and old patients' tissues. The possible interventions are selected and rated according to their ability to regulate age-related changes and minimize differences in the signaling pathway cloud. This flexible and scalable approach may be used to predict the efficacy of the many drugs that may extend human longevity before conducting pre-clinical work and expensive clinical trials.

Link: http://journal.frontiersin.org/Journal/10.3389/fgene.2014.00049/abstract

The best understood activity of the enzyme telomerase is that it lengthens telomeres, the repeating DNA sequences at the end of chromosomes that form a part of the mechanism to limit the number of times a cell can divide. Average telomere length in tissues is very dynamic, a reflection of the interplay of numerous processes that lengthen and shorten telomeres or change the number of cells with long versus short telomeres. The average tends to fall with ill health and age, which is how work on telomerase-enhancing treatments started, with the aim of reversing this signature in the hope that it will improve matters.

My take on reduced telomere length is that it is a consequence of damage and dysfunction, not a primary cause of aging - though it might have further detrimental effects once it exists. The principle counterpoint to that position is that telomerase enhancement in mice lengthens life. So either I'm wrong or one of the other activities of telomerase is significant, such as interactions between telomerase and mitochondria.

This open access review is a fair summary of the arguments to try increasing the activity of telomerase in humans. Note that many of the groups most vocal on this topic at the moment are selling supplements or herbal extracts backed by sketchy or irrelevant data, the usual modus operandi in the "anti-aging" industry, and an annoyance for anyone looking for serious scientific work on targeting telomerase - so take everything that contingent has to say with a grain of salt:

The elderly population is increasing progressively. Along with this increase the number of age related diseases, such as cardiovascular, neurodegenerative diseases, metabolic impairment and cancer, is also on the rise thereby negatively impacting the burden on health care systems. Telomere shortening and dysfunction results in cellular senescence, an irreversible proliferative arrest that has been suggested to promote organismal aging and disabling age-related diseases.

Given that telomerase, the enzyme responsible for maintaining telomere lengths, is not expressed at levels sufficient to prevent telomere shortening in most of our cells, telomeres progressively erode with advancing age. Telomerase activation, therefore, might serve as a viable therapeutic strategy to delay the onset of cellular senescence, tissue dysfunction and organismal decline. Here we analyze the more recent findings in telomerase activation as a potential key modulator for human healthspan and longevity.

Link: http://dx.doi.org/10.1016/j.arr.2013.12.006

Animal data comprehensively demonstrates that regular exercise improves long-term health. The data on life extension is less conclusive, but in some studies more individuals lived into what is the late life period for their species, extending mean life span. Other studies show no such increase. Researchers can follow groups of animals for their entire life spans and crunch the numbers: the causality of results can be well demonstrated, and we can safely conclude that exercise is producing these benefits.

In human studies statistics and population surveys have to substitute for following groups carefully segregated by amount of exercise, with scientific controls and consistent data gathering, for an entire life span. It is very hard to pull causality from this sort of data, but the data itself looks very similar to that generated in animal studies, in that regular exercise is a good thing for health and produces analogous short term changes in measures of metabolism. It isn't unreasonable to expect on the basis of all this evidence that regular exercise does indeed cause better health, on balance, across populations, in humans just as it does in animals.

All this has been said numerous times, and there are mountains of data to support it. You should be exercising, as your physician no doubt reminds you on every occasion that the two of you meet: it costs little and produces greater benefits for most people than any sort of presently available medical technology. There is so much epidemiological data on exercise available in this age of cheap computing that anyone with the time and skills can slice and dice it to come up with new measures - such as a guesstimate of the return on investment for exercise. What is the expected outcome in terms of time gained versus time invested? This will not be a simple linear relationship, but it is interesting to come up with simple speculative numbers - and bear in mind that it isn't just life gained, but also medical expenditures and pain and suffering reduced:

Every Minute Of Exercise Could Lengthen Your Life Seven Minutes

It's a daily struggle to make the time to exercise, and the current federal health guidelines call for at least 150 minutes a week of moderate exercise - a lot of time that somehow manages to seem like even more, magnified by the "should" it adds to so many days. There are hundreds of other reasons to exercise, and the one that works best for me is wanting to feel at my best on that very day. But it would be very comforting, I thought, if I knew that all of that time would come back to me.

Let me cut to the happy conclusion: It seems that it does. And then some. If you play with the data of a recent major paper on exercise and longevity, you can calculate that not only do you get the time back; it comes back to you multiplied - possibly by as much as seven or eight or nine.

Pooled data from six large studies that included more than 650,000 people followed over ten years [showed] that people who exercised at the recommended level gained 3.4 years of life after age 40. Say you start with someone 45 years old who begins to follow the 150-minute-a-week recommendation. Average American life expectancy is 78. So: "If you start exercising at 45 and you die at 78, that means that you exercise for 33 years, at 150 minutes a week. I calculated that over 33 years you would need to spend basically 4,290 hours in exercise, which is 179 days of exercise, which is less than half a year. So that's half a year, and you gain almost three and a half years, so it is worth exercising. That's an approximate scenario using reasonable assumptions, and you're getting a 1-to-7 return.

On the flip side of the coin, there is the now fairly established ballpark estimate that being sedentary is about as bad as smoking when it comes to the bottom line of whether you are going to be alive or dead or dying some number of years from now:

Lack of exercise kills roughly as many as smoking, study says

People across the world are falling so far short on exercise that the problem has become a global pandemic, causing nearly a tenth of deaths worldwide and killing roughly as many people as smoking, researchers warned this week. Eight out of 10 youngsters age 13 to 15 don't get enough exercise [and] nearly a third of adults fall short. The problem is even worse for girls and women, who are less active than boys and men, researchers found.

The results are fatal. Lack of exercise is tied to worldwide killers such as heart disease, diabetes and breast and colon cancer. If just a quarter of inactive adults got enough exercise, more than 1.3 million deaths could be prevented worldwide annually, researchers said. Half an hour of brisk walking five times a week would do the trick.

SENS, the Strategies for Engineered Negligible Senescence, provides an overview of the causes of aging and detailed research plans aimed at the production of repair therapies that can reverse those causes. This is all drawn from and built atop past decades of work in many life science fields relevant to medicine.

Every other year for the past decade a SENS conference has been held: a way to look at progress, make connections, and draw new scientists into the field. You'll find an array of presentation videos from last year's SENS6 conference on rejuvenation biotechnology at the SENS Research Foundation. If you have a few hours to spare then take some time to browse, as this is a very good way to gain an impression of the state of this comparatively young field of medical research as it stands today:

The SENS6: Reimage Aging Conference in September of 2013 marked the sixth conference held at historic Queens' College at the University of Cambridge. World-renowned scientists and other visionaries in the field of regenerative medicine presented the latest cutting-edge advances in regenerative medicine and biotechnology. Here you can view an overview of the conference as well as selected presentations and interviews. See why many remarked that it was the best SENS Conference to date.

Link: http://sens.org/videos/sens6-reimagine-aging-conference

This research is worth noting as a measure of the relative importance of visceral fat to long-term health. The more of it you have the worse off you are:

[Researchers] developed a new method to quantify the risk specifically associated with abdominal obesity. A follow-up study [supports] their contention that the technique, known as A Body Shape Index (ABSI), is a more effective predictor of mortality than Body Mass Index (BMI), the most common measure used to define obesity.

The team analyzed data for 7,011 adults, 18+, who participated in the first Health and Lifestyle Survey (HALS1), conducted in Great Britain in the mid 1980s, and a follow-up survey seven years later (HALS2). The sample was broadly representative of the British population in terms of region, employment status, national origin, and age. They used National Health Service records through 2009 to identify deaths and cancer cases: 2,203 deaths were recorded among the sample population.

The analysis found ABSI to be a strong indicator of mortality hazard among the HALS population. Death rates increased by a factor of 1.13 for each standard deviation increase in ABSI. Persons with ABSI in the top 20 percent were found to have death rates 61 percent higher than those with ABSI in the bottom 20 percent.

Link: http://www.ccny.cuny.edu/news/body-shape-index-study.cfm

We live in a time of accelerating change, the opening decades of a biotechnology revolution driven by rapid growth in communications and computing power. A single laboratory can achieve in months today what would have taken years and much of the research community twenty years ago. New capabilities in medicine are demonstrated in the laboratory with ever increasing frequency, and hidebound institutions that presently try to enforce extremely long development cycles for new treatments cannot survive for much longer - not when valuable potential applications of new medical technology pile up ever higher year after year. There is a broad world out there, and new therapies will be commercially developed in those regions that smooth the way rather than throwing up barriers to rapid innovation - and these new therapies will in due course include the first practical treatments to repair some of the causes of degenerative aging.

David Gobel is co-founder and CEO of the Methuselah Foundation, an organization that has influenced many of the most important changes in the culture and progress of longevity science over the past decade. He sees tissue engineering as an important engine in the years ahead, bioprinting especially, with the ultimate goal of generating patient-matched new organs from scratch as needed. This is a part of the acceleration of progress in biotechnology and its application to medicine, and Gobel made that point in this post to the Gerontology Research Group list:

Gentlemen, a single scribe would labor for 20 years to produce a single cathedral worthy Bible - his life's work - if he lived that long. We live in the scribal age of medicine where solutions take 20 years to achieve. The printing press reduced 20 years to 20 months, 20 days, hours, minutes, seconds, etc, etc. What we now actually have is a new printing press for micro and macro tissues such that profoundly confounding structures might be reduced and reproduced at will, in perfection and in such quantity as to make costs 17 years hence a mere trifle comparatively.

When we became first investor in Organovo, this was our vision. New parts for people. Simple, direct, engineering, we may not know in detail why it all works, but work it does (so far). In December we with the advice and support of our science advisors launched the $1,000,000 New Organ Liver Prize. This year we are investigating with our partners two additional prize challenges on bioengineering hearts and preserving whole organs. Methuselah also offers $500,000 to qualified fearless tissue engineering researchers to secure access to one of Organovo's printers as well as training, support, startup funds and supplies. We are as they say "all in" on this hand.

Till now, medical research reminds one of 16th century alchemy seeking the elixir of life by error and trials. It is time for a biological industrial revolution where the body and bodies of humanity itself are the direct beneficiary. We do indeed believe that 3D tissue printing will make major contributions to extending healthy lifespan by accelerating and improving toxicology models, pathology models, replacement tissues, and finally new organs. We expect that such advances will begin this very year with toxicology models, and that advances will accelerate and a new industry arise such that by 2018 (we hope) and 2021 (feel certain) that large and complex macro tissue systems will be available for experimental insertion and use in large mammals.

Shortly thereafter it is our hope that the SENS portfolio and similar efforts in rejuvenation will begin to come on stream to repair the molecular damage of our decaying selves. SENS is a firebreak for our futures.

You might recall that SENS research programs were first funded and organized under the Methuselah Foundation umbrella before the SENS Research Foundation launched as an independent organization back in 2009.

In recent years some progress has been made towards the distinct goals of complete regeneration of a damaged liver in situ and the creation of new livers on demand for transplantation. Here, researchers demonstrate the ability to generate a patient-matched source of liver cells for repair purposes:

In previous studies on liver-cell reprogramming, scientists had difficulty getting stem cell-derived liver cells to survive once being transplanted into existing liver tissue. Writing in the latest issue of the journal Nature, researchers reveal a new cellular reprogramming method that transforms human skin cells into liver cells that are virtually indistinguishable from the cells that make up native liver tissue.

"Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order to then grow liver cells. However, generating these so-called induced pluripotent stem cells, or iPS cells, and then transforming them into liver cells wasn't always resulting in complete transformation. So we thought that, rather than taking these skin cells all the way back to a pluripotent, stem cell-like state, perhaps we could take them to an intermediate phase."

This research [involved] using a 'cocktail' of reprogramming genes and chemical compounds to transform human skin cells into cells that resembled the endoderm. Endoderm cells are cells that eventually mature into many of the body's major organs - including the liver. Next, the researchers discovered a set of genes and compounds that can transform these cells into functioning liver cells. And after just a few weeks, the team began to notice a transformation. Now that the team was encouraged by these initial results in a dish, they wanted to see what would happen in an actual liver. So, they transplanted these early-stage liver cells into the livers of mice. Over a period of nine months, the team monitored cell function and growth by measuring levels of liver-specific proteins and genes.

Two months post-transplantation, the team noticed a boost in human liver protein levels in the mice, an indication that the transplanted cells were becoming mature, functional liver cells. Nine months later, cell growth had shown no signs of slowing down. These results indicate that the researchers have found the factors required to successfully regenerate liver tissue.

Link: http://www.eurekalert.org/pub_releases/2014-02/gi-sts021814.php

Death is Wrong is a child's primer on efforts to develop treatments for degenerative aging, so as to prevent the enormous toll of suffering and death it causes. Here the author is raising funds to distribute copies to activists for longevity science. The ongoing process of persuading the world to take an interest in and provide sufficient support for building a cure for aging is made of many such modest steps:

Death is Wrong fills an important void and can inspire a new generation to join the struggle for greatly increased longevity. Virtually everyone learns about death as a child, and the initial reaction is the correct one: bewilderment, horror, and outrage. Yet there has been no resource to validate these completely correct first impressions. Almost immediately, the young ones are met with excuses and rationalizations, so that they might be consoled and return to a semblance of normalcy. Over millennia of facing indeed inevitable demises, humans have constructed elaborate edifices of rationalization, designed to keep thoughts of death from intruding upon their day-to-day lives.

While transhumanists and life-extension advocates have made headway with conveying their aspirations for the future to some of the most technically educated and philosophically inclined adults, the mainstream of society remains pervaded by the old death-acceptance arguments - religious and secular: from the fear of "playing God" to the specter of overpopulation. Every mind held captive by these traditional and Malthusian pro-death prejudices is a mind that will at best not help life-extension progress and at worst hinder it greatly - a higher likelihood for the most intelligent purveyors of the death-acceptance mindset. People who embrace these notions and find them credible (despite the relative ease of debunking them using logic and evidence) largely do so because the fallacies were ingrained into them since childhood, with no counterarguments being presented or even posited as conceivable. So, if the antidote to these fallacies is to be most effective, it must be administered in childhood.

Death is Wrong will be easily understood by most eight-year-olds, though my aim is to encompass as young an audience as possible. The beautiful and detailed illustrations will help keep young minds engaged as they read about long-lived organisms found in nature, as well as the great advocates of life extension from the past and the present. The book discusses successes in animal life extension, along with providing a concise introduction to Dr. de Grey's SENS program and the seven principal types of damage that must be addressed in order to reverse senescence. The book also focuses of refuting the common pro-death rationalizations and presenting young readers with all of the amazing opportunities and possibilities that can only exist if humans live much, much longer than is presently the case. At the end is a call to action and a list of further resources for young readers to find out more and to become involved with the life-extension movement.

Link: http://www.indiegogo.com/projects/help-teach-1000-kids-that-death-is-wrong

Here is a copy of a recent arrival in my in-box from the SENS Research Foundation, currently the world's most important research organization when it comes to work on the foundations of near-future rejuvenation biotechnologies, ways to repair the known forms of cellular and molecular damage that cause degenerative aging. The section on mitochondrial damage repair is well worth reading:

Full Series of SRF Education Coursework Videos Now Online

SRF asked world-renowned researchers to participate in a series of lecture videos explaining how regenerative medicine can help treat and prevent the diseases of aging. We are happy to announce that the 10-part series of videos is now complete and available on the SRF website.

Learn more about stem cells, tissue engineering, cancer mitigation strategies and regenerative medicine from such luminaries as Dr. Daniel Kraft, Dr. Alan Russell, Dr. Judith Campisi, and Dr. Michael West on our Video Lecture Course
page.

Supporter Profile: Jason Hope

1) How did you become interested in SENS Research Foundation's work?

It really started for me once I read the book "The Singularity Is Near" by Ray Kurzweil. It made me realize that we advanced technology so fast that we really left ourselves behind. I spent some time researching technology in the health industry and came across Dr. Aubrey de Grey. I quickly realized his unique engineering approach to fighting the diseases of aging was exactly what we needed to finally solve some of today's biggest killers and drivers of healthcare costs, including heart disease, stroke, and cancer.

2) Why do you think it is important for people to support SENS Research Foundation?

Although hundreds of billions of dollars have been poured into biotech and healthcare research over the past several decades, not much has changed about how we approach solving our biggest health problems. The wars on heart disease and cancer are far from over and little progress has been made against these diseases. SENS gives us a new approach that stands to alleviate a significant amount of human suffering in the near future. SRF's cutting edge research is going to really move us forward. It's going to give us and our loved ones the ability to live longer, healthier lives and the more people that get involved, the faster this becomes a reality.

Question Of The Month #1: How To Manage Mutant Mitochondria?

SRF is pleased to present a new monthly column. Expert science writer Michael Rae will answer one question from our inbox each month. Please send your questions to foundation@sens.org and your question may be featured.

Q: Dr. De Grey says in his Mitochondrial Mutations in Aging video that there are three principal ways to solve the problem of eliminating mitochondria with mutated DNA, but what seems to me the most straightforward method is not discussed. Why not simply selectively target the mutated mitochondria (since we can clearly identify them) and tag them for mitochondrial autophagy (by inducing damage, etc.) and thus selectively destroy the mutated organelles?

A: In principle, your proposal would be a great solution, but the key would be to find a way to selectively target mutant mitochondria, and there are no known ways of doing so at present. First, while it's true that we can identify such damaged mitochondria, we can only do so in cells isolated from the body and stained with various dyes, or heated up to break down the DNA into smaller chunks that are then analyzed -- not while those cells and tissues are still present and carrying out their function inside a person's living body.

As yet, there is no known signal put out by mitochondria harboring large deletions (the main class of mutations that accumulate in aging cells) that we could use for the purpose you describe. That's all the more true since such mitochondria are minimally metabolically active and can no longer produce their own proteins.

Second, there's good reason to think that the endogenous way of tagging defective mitochondria for destruction in the lysosome actually drives the problem! You can read the details in Ending Aging, but under a model Dr. de Grey nicknamed "Survival of the Slowest," cells identify old, damaged, but non-mutant mitochondria by the damage they accumulate in their membranes from the free radicals that they are constantly producing. By contrast, mitochondria bearing these deletion mutations avoid destruction because they no longer have the ability to produce key proteins in their energy-producing machinery. Without these proteins, the main mechanism of energy production in mitochondria shuts down - and along with it, free radical generation ceases. In the absence of the constant bombardment of free radicals, these mutant mitochondria no longer suffer damage to their membranes, and as a result, they they evade the normal mechanism that would target them for destruction. Mutated mitochondrial DNA then accumulates, as only non-mutant mitochondria are consumed.

Once the first mitochondrion in a cell suffers a deletion mutation, this process appears to lead very rapidly to the elimination of all of the non-mutant mitochondria in the cell, leaving behind a cell completely taken over by mutants. We never find cells in a state of transition between all-healthy and all-mutant mitochondria.

Any system that therefore aims to prevent the expansion of mutation-bearing mitochondria would have to cull deletion-bearing mitochondria faster than the normal processes of mitophagy already apparently culls healthy ones. This system would have to be thorough enough - and durable enough - to prevent the selective "clonal expansion" from happening indefinitely, under the full range of metabolic states of the cell. Next, we'd have to ensure that this dual culling would not somehow harm the cell: this doesn't seem likely, since the mutant mitochondria are by their nature harmful, but it would have to be tested.

I can see at least two ways that a system used to identify mutation-bearing mitochondria and send them to the lysosome for disposal might be subverted over time. First, the system might require us to insert new genes into the mitochondria (to express a marker under conditions where the activity of certain components of the citric acid cycle were very high, for instance). But since the whole problem is that such genes can be mutated, it's likely that many mutation-bearing mitochondria (again, particularly the most important class, which bear large deletions) would have mutations that inactivate these very genes. Secondly, the signal tag itself could be degraded or damaged while the mutation-bearing mitochondrion is awaiting disposal.

The advantage of the approaches that we favor is that they bypass the need for the mitochondria to behave in any particular way (such as to express any particular protein or produce any particular metabolite), and make the presence or absence of deletions in the mitochondrial DNA irrelevant to the body. Because we will engineer an alternative means of getting the mitochondria's energy-producing machinery the proteins it needs to function normally (whether by putting backup copies in the nucleus, or by delivering the needed RNAs directly into the mitochondria), the mitochondria will function normally whether they have deletions or not. This means that deletion-bearing mitochondria (a) can keep producing energy in the cell, (b) don't cause the cell to produce the toxins that they normally do, and thus avoid poisoning the rest of the body, and (c) will once again be subject the standard mechanism of clearing damaged mitochondria out of the cell thereby effecting what you propose by a circuitous route.

REMINDER: SRF Summer Scholars Program Applications Due March 3

The search for undergraduates to participate in the 2014 SRF Summer Scholars Program continues. If you are a qualifying student (click here for eligibility guidelines), make sure to submit your application before the deadline of 12 AM PST on March 3, 2014.

If you know an undergrad who might be interested in participating, make sure and alert them to this paid opportunity to join researchers at several distinguished institutions, including SENS Research Foundation's own Research Center, to tackle the diseases of aging.

Again, the application period ends at 12 AM PST on March 3, 2014. No applications will be accepted after the deadline.To learn more, visit http://sens.org/2014-summer-scholars.

New SENS6 Video Content: Translational Research Challenges and More

New video presentations from the SENS6: Reimagine Aging Conference are now available. In addition to Dr. George Church's keynote address outlining the latest advances in genomics and -ome technology, you can now also view Richard Barker's presentation on the challenges facing translational research, Dr. Brian O'Nuallain's talk on the therapeutic and diagnostic potential of innate and vaccine-generated antibodies, and others here on our SENS6: Reimagine Aging Conference Videos page.

Do you like what you see here? Then donate to help support the work of the SENS Research Foundation. You can look at the organization's annual reports to see where your funds will go, which is largely to specific research projects needed to develop means of rejuvenation. Life science and biotechnology research is becoming cheaper with every passing year, and even small sums make a big difference by enabling incremental new projects that move us all closer to the day on which actual, working rejuvenation treatments come into being. There are precious few opportunities for people like you and I to make such a large difference to the future of health and longevity - so seize this one.

Wearable accelerometers are a comparatively new development in studies of the effects of exercise and activity on health. One of the outcomes is better evidence to suggest that even activities that don't rise to the level of what most people would consider exercise do in fact make a difference - standing versus sitting, for example:

If you're 60 and older, every additional hour a day you spend sitting is linked to a 50 percent greater risk of being disabled - regardless of how much moderate exercise you get, The study is the first to show sedentary behavior is its own risk factor for disability, separate from lack of moderate vigorous physical activity. In fact, sedentary behavior is almost as strong a risk factor for disability as lack of moderate exercise. If there are two 65-year-old women, one sedentary for 12 hours a day and another sedentary for 13 hours a day, the second one is 50 percent more likely to be disabled, the study found.

The study focused on a sample of 2,286 adults aged 60 and older from the National Health and Nutrition Examination Survey. It compared people in similar health with the same amount of moderate vigorous activity. Moderate activity is walking briskly, as if you are late to an appointment.

The participants wore accelerometers from 2002 to 2005 to measure their sedentary time and moderate vigorous physical activity. The accelerometer monitoring is significant because it is objective. The older and heavier people are, the more they tend to overestimate their physical activity. Previous research indicated a relationship between sedentary behavior and disability but it was based on self-reports and, thus, couldn't be verified.

Because the study examines data at one point in time, it doesn't definitively determine sedentary behavior causes disability. "It draws attention to the fact that this is a potential problem." Studies with animals have shown immobility is a separate risk factor for negative effects on health. "This is the first piece of objective evidence that corroborates the animal data."

This is the way things usually go: causality is determined in animal studies, where you can set a parameter and see what happens, but human studies largely only produce statistical correlations. Where those correlations match up with data generated in animal studies, that is good evidence to suggest that the same causality is at work in humans.

Link: http://www.northwestern.edu/newscenter/stories/2014/02/new-sitting-risk-disability-after-60.html

An interesting relationship between cellular maintenance machinery and age-related issues with sleep is uncovered and partially reversed by researchers here - though I would like to see more work on this topic before going along with their interpretation as to what is happening under the hood:

[Scientists] have been studying the molecular mechanisms underpinning sleep. Now they report that the pathways of aging and sleep intersect at the circuitry of a cellular stress response pathway, and that by tinkering with those connections, it may be possible to alter sleep patterns in the aged for the better - at least in fruit flies.

Increasing age is well known to disrupt sleep patterns in all sorts of ways. Aging is associated with increasing levels of protein unfolding, a hallmark of cellular stress called the "unfolded protein response." Protein misfolding is also a characteristic of several age-related neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, and as it turns out, also associated with sleep deprivation. [The researchers] wanted to know if rescuing proper protein folding behavior might counter some of the detrimental sleep patterns in elderly individuals.

They found that aged flies took longer to recover from sleep deprivation, slept less overall, and had their sleep more frequently interrupted compared to younger control animals. However, adding a molecule that promotes proper protein folding - a molecular "chaperone" called PBA - mitigated many of those effects, effectively giving the flies a more youthful sleep pattern. PBA (sodium 4-phenylbutyrate) is a compound currently used to treat such protein-misfolding-based diseases as Parkinson's and cystic fibrosis. Molecular analysis of sleep-deprived and PBA-treated flies suggested that PBA acts through the unfolded protein response.

The team also asked the converse question: Can protein misfolding induce altered sleep patterns in young animals. Another drug, tunicamycin, induces protein misfolding and stress, and when the team fed it to young flies, their sleep patterns shifted towards those of aged flies, with less sleep overall, more interrupted sleep at night, and longer recovery from sleep deprivation.

Link: http://www.eurekalert.org/pub_releases/2014-02/uops-sif022014.php

One of the ways in which people dismiss modern, legitimate research aimed at extending healthy human life is to decry it as just more of the same fraud, wishful thinking, and lies that have accompanied the desire for restored youth throughout history. It is certainly true that there is a lot of fraud and misrepresentation out there: the largest megaphones in the matter of aging and longevity are wielded by supplement sellers and the like. These are people with no incentive to be truthful and accurate, and who suffer few if any repercussions for stretching facts and scientific findings to breaking point, and it shows. The public spends billions on what is in essence fairy dust and fairy tales, while largely shunning the realistic research programs that might actually achieve extension of life. Never let it be said that we live in a sane world.

Is it really the case that nothing besides fraud and lies emerged from the desire for longevity all the way up until the point at which it became possible to actually start to do something about degenerative aging? That point in the development of biotechnology was arguably only reached perhaps thirty years ago at most, and meaningful initiatives - such as SENS research - only began in the last decade or so. The life sciences as practiced under the modern understanding of the scientific method have a history of several centuries of good, organized work, however.

A point argued in the paper quoted below is that the urge to longevity, while not generating actual means of rejuvenation, given that the technologies and knowledge needed to work usefully towards that goal did not exist until very recently, nonetheless led to the production of useful and even important advances in medicine.

The unexpected outcomes of anti-aging, rejuvenation and life extension studies: an origin of modern therapies

The search for life-extending interventions has been often perceived as a purely academic pursuit, or as an unorthodox medical enterprise, with little or no practical outcome. Yet, in fact, these studies, explicitly aiming to prolong human life, often constituted a formidable, though hardly ever acknowledged, motivation for biomedical research and discovery.

At least several modern biomedical fields have directly originated from rejuvenation and life extension research: 1) Hormone Replacement Therapy was born in Charles-Edouard Brown-Séquard's rejuvenation experiments with animal gland extracts (1889). 2) Probiotic diets originated in Elie Metchnikoff's conception of radically prolonged "orthobiosis" (c. 1900). 3) The development of clinical endocrinology owed much to Eugen Steinach's "endocrine rejuvenation" operations (c. 1910s-1920s). 4) Tissue transplantations in humans (allografts and xenografts) were first widely performed in Serge Voronoff's "rejuvenation by grafting" experiments (c. 1910s-1920s). 5) Tissue engineering was pioneered during Alexis Carrel's work on cell and tissue immortalization (c. 1900-1920). 6) Cell therapy (and particularly human embryonic cell therapy) was first widely conducted by Paul Niehans for the purposes of rejuvenation as early as the 1930s.

Thus, the pursuit of life extension and rejuvenation has constituted an inseparable and crucial element in the history of biomedicine. Notably, the common principle of these studies was the proactive maintenance of stable, long-term homeostasis of the entire organism.

The goals haven't changed: what has changed is that we can now outline in detail exactly how to achieve the goal of indefinite homeostasis for a complex organism, based on repair of the damage that causes change and degeneration.

I have mixed feelings about holding up hormone replacement therapy (HRT) and probiotics as exemplars here, given their abuse at the hands of the "anti-aging" marketplace and similar unhelpful entities. But we should remember that HRT is a useful treatment for a narrow range of comparatively rare medical conditions that can cause considerable suffering. Similarly for probiotics. But neither seem particularly beneficial or useful as a general palliative treatment for aging, based upon the research consensus. In comparison to SENS-style targeted applications of cutting-edge molecular biology aimed at very narrowly defined forms of cellular damage, HRT and probiotics might as well be lumped together in the technology pyramid at the same level as apes banging rocks together. Though of course you won't get that message from the people in the "anti-aging" industry trying to sell you on their treatments.

The next generation of cancer treatments will be targeted approaches that destroy only cancer cells, with few or no side-effects. Given the results of the past decade of work, it looks likely that a majority of these treatments will be immune therapies, in which a patient's immune cells are engineered or trained to identify and attack the cancer. Clinical trials for a few such therapies are ongoing, mixed in with established treatment options. This is an example one of the more effective applications to date:

The largest clinical study ever conducted to date of patients with advanced leukemia found that 88 percent achieved complete remissions after being treated with genetically modified versions of their own immune cells. "These extraordinary results demonstrate that cell therapy is a powerful treatment for patients who have exhausted all conventional therapies. Our initial findings have held up in a larger cohort of patients, and we are already looking at new clinical studies to advance this novel therapeutic approach in fighting cancer."

Adult B cell acute lymphoblastic leukemia (B-ALL), a type of blood cancer that develops in B cells, is difficult to treat because the majority of patients relapse. Patients with relapsed B-ALL have few treatment options; only 30 percent respond to salvage chemotherapy. Without a successful bone marrow transplant, few have any hope of long-term survival.

In the current study, 16 patients with relapsed B-ALL were given an infusion of their own genetically modified immune cells, called T cells. The cells were "reeducated" to recognize and destroy cancer cells that contain the protein CD19. While the overall complete response rate for all patients was 88 percent, even those with detectable disease prior to treatment had a complete response rate of 78 percent, far exceeding the complete response rate of salvage chemotherapy alone.

In the current study, seven of the 16 patients (44 percent) were able to successfully undergo bone marrow transplantation - the standard of care and the only curative option for B-ALL patients - following treatment. Three patients were ineligible due to failure to achieve a complete remission, three were ineligible due to preexisting medical conditions, two declined, and one is still being evaluated for a potential bone marrow transplant. Historically, only 5 percent of patients with relapsed B-ALL have been able to transition to bone marrow transplantation.

Link: http://www.mskcc.org/pressroom/press/cell-therapy-shows-remarkable-ability-eradicate-clinical-study

These researchers put forward a theory of programmed aging that is based on the interactions between RNA populations and the genome. At present the mainstream view is that aging is not programmed, but rather a matter of stochastic accumulation of damage and the reactions to that damage - therefore developing methods of repair is the best way to prevent and reverse aging. No view in a developing field is ever shared universally of course:

Aging individuals can no longer maintain homeostasis in response to physiologic and environmental changes as easily as they once could. Through the years, copious hypotheses have been proposed to explain the mechanisms of aging. These hypotheses include two main types: one is an orderly, genetically programmed event that is the consequence of differentiation, growth, and maturation; the other is a stochastic event resulting from accumulation of random errors. However, each type of hypothesis cannot independently explain aging.

We propose the RNA population model as a genetic theory of aging. The new model can also be applied to differentiation and tumorigenesis and could explain the biological significance of non-coding DNA, RNA, and repetitive sequence DNA.

The RNA population in a cell is comprised of all of its transcriptional RNAs. The RNAs produced from a single transcription site (including multiple genes) make up an RNA subpopulation that forms a local network via RNA repetitive sequence complementation. Interactions between DNA and RNA in the local network disturb the tight packing of chromatin and maintain gene activation. In contrast, RNA fragments that destroy the RNA network or that disturb the interaction between DNA and the network RNA inhibit gene transcription. Gene transcription resulting from the interaction between DNA and the RNA network produces an RNA population that, in turn, affects gene transcription via changing chromatin packing in cell division. Gene transcription can be altered by changes in the interactions between the RNA population and DNA. Such changes are the foundation of aging and differentiation. If the interaction between the RNA population and DNA runs a cyclical course, it would result in immortal cells.

Link: http://dx.doi.org/10.1016/j.arr.2013.11.001

Perhaps the greatest technical challenge in tissue engineering is the matter of blood vessels. The cells in any tissue larger than a sliver must be supported by a network of capillaries and larger blood vessels, and putting those in place isn't a simple undertaking. This is one of the principal reasons why decellularization is such an attractive option for engineering organs and large tissue sections: the decellularized donor organ provides a scaffolding of blood vessel networks and other structures, along with chemical cues necessary to guide the right cells to the right places.

Reproducing these intricacies in sufficient detail from scratch is currently beyond the capabilities of the scientific community, but people are working on it. Over the next decade, we should expect to see increasingly sophisticated, competing efforts to produce complex scaffolds and structure in tissue engineering. More importantly there will be efforts to make this a reliable and low-cost process - scalable infrastructure is the more important part of the equation here. This is all taking place right now and has been for years; progress is being made, as this is a comparatively well-funded field.

3-D printing technologies show a great deal of promise for tissue engineering, as there is already a large and mature industry devoted to modeling and printing detailed structures in various materials. Companies such as Organovo have made inroads in this area over the past decade, but there is a great deal of work yet to accomplish. These are still the early days for tissue printing. To pick an example of the present state of the art, this recent article looks at one research group and their approach to generating blood vessel networks in bioprinted tissues. As it notes, the near term goal is not tissues for transplantation, but to obtain a result that is sufficiently close to the real thing for use in drug and toxicity testing:

An essential step toward printing living tissues

A new bioprinting method [creates] intricately patterned, three-dimensional tissue constructs with multiple types of cells and tiny blood vessels. The work represents a major step toward a longstanding goal of tissue engineers: creating human tissue constructs realistic enough to test drug safety and effectiveness. To print 3D tissue constructs with a predefined pattern, the researchers needed functional inks with useful biological properties, so they developed several "bio-inks" - tissue-friendly inks containing key ingredients of living tissues. One ink contained extracellular matrix, the biological material that knits cells into tissues. A second ink contained both extracellular matrix and living cells.

To create blood vessels, they developed a third ink with an unusual property: it melts as it cools, rather than as it warms. This allowed the scientists to first print an interconnected network of filaments, then melt them by chilling the material and suction the liquid out to create a network of hollow tubes, or vessels.

[The] team then road-tested the method to assess its power and versatility. They printed 3D tissue constructs with a variety of architectures, culminating in an intricately patterned construct containing blood vessels and three different types of cells - a structure approaching the complexity of solid tissues. Moreover, when they injected human endothelial cells into the vascular network, those cells regrew the blood-vessel lining. Keeping cells alive and growing in the tissue construct represents an important step toward printing human tissues. "Ideally, we want biology to do as much of the job of as possible."

At the high level aging is defined as an increase in mortality rate with time due to intrinsic causes. By this definition some species become "immortal" in old age: their mortality rates grow to become high but then cease to rise further in the final stage of life. The best data for this effect has been gathered in flies, and a lot of theorizing has taken place on what this might mean for the evolution of aging.

Finding this same effect in humans is a more challenging undertaking, as the data for human aging in extreme old age is sparse. The number crunching to date has leaned strongly towards there being no slowing of the increase in mortality rate over time in humans, and certainly no late life mortality plateau of the sort that occurs in flies. Here is a recent publication on this topic:

The growing number of persons living beyond age 80 underscores the need for accurate measurement of mortality at advanced ages and understanding the old-age mortality trajectories. It is believed that exponential growth of mortality with age (Gompertz law) is followed by a period of deceleration, with slower rates of mortality increase at older ages. This pattern of mortality deceleration is traditionally described by the logistic (Kannisto) model, which is considered as an alternative to the Gompertz model.

Mortality deceleration was observed for many invertebrate species, but the evidence for mammals is controversial. We compared the performance (goodness-of-fit) of two competing models - the Gompertz model and the logistic (Kannisto) model using data for three mammalian species: 22 birth cohorts of U.S. men and women, eight cohorts of laboratory mice, and 10 cohorts of laboratory rats. For all three mammalian species, the Gompertz model fits mortality data significantly better than the "mortality deceleration" Kannisto model (according to the Akaike's information criterion as the goodness-of-fit measure). These results suggest that mortality deceleration at advanced ages is not a universal phenomenon, and survival of mammalian species follows the Gompertz law up to very old ages.

Link: http://dx.doi.org/10.1093/gerona/glu009

It is thought that mitochondrial DNA damage - and consequent mitochondrial dysfunction - is a contributing cause of aging. There is plenty of evidence to support that view, but it still lacks the sort of conclusive proof needed to sink all arguments, such as engineering longer life for laboratory animals through mitochondrial DNA repair, something that will soon be possible. Here, researchers look at specific forms of age-related mitochondrial change in nematodes and suggest that they are consequences, not causes of aging:

Mitochondrial dysfunction is a hallmark of skeletal muscle degeneration during aging. One mechanism through which mitochondrial dysfunction can be caused is through changes in mitochondrial morphology. To determine the role of mitochondrial morphology changes in age-dependent mitochondrial dysfunction, we studied mitochondrial morphology in body wall muscles of the nematode C. elegans.

We found that in this tissue, animals display a tubular mitochondrial network, which fragments with increasing age. This fragmentation is accompanied by a decrease in mitochondrial volume. Mitochondrial fragmentation and volume loss occur faster under conditions that shorten lifespan and occur slower under conditions that increase lifespan. However, neither mitochondrial morphology nor mitochondrial volume of five- and seven-day old wild-type animals can be used to predict individual lifespan.

Our results indicate that while mitochondria in body wall muscles undergo age-dependent fragmentation and a loss in volume, these changes are not the cause of aging but rather a consequence of the aging process.

Link: http://www.impactaging.com/papers/v6/n2/full/100639.html

Heat shock proteins such as HSP70 are a component of the cellular response to stress: they are generated in greater amounts when a cell is exposed to heat, toxins, starvation, and so forth. They have numerous important roles, but the roles of interest here involve protein quality control, activities that include ensuring that protein machinery folds correctly and misfolded proteins are quickly disposed of before they can cause harm. Misfolded and otherwise broken proteins are a form of damage, and the better the maintenance the less damage there is to impact cells and the organism to which those cells belong.

Heat shock protein activity is thus a noteworthy part of the hormetic response to mild levels of stress, something that contributes to the long-term benefits of calorie restriction, exercise, mild irradiation, and so forth. All of these things spur cells to undertake greater maintenance activities for a period of time, which results in a net benefit. If trying to create a therapy based on mimicking generalized increased levels of hormesis, then boosting levels of heat shock proteins might be a starting point. The mainstream research community hasn't headed in that direction yet with anywhere near the enthusiasm demonstrated for calorie restriction mimetics, however.

Here is an interesting primate study that shows HSP70 levels to predict growth in insulin resistance years later. Given that excess fat tissue and lack of exercise are just as involved as aging in rising insulin resistance in we humans, that raises a number of questions as what is going on here:

Muscle Heat Shock Protein 70 Predicts Insulin Resistance With Aging

Heat shock protein 70 (HSP70) protects cells from accumulating damaged proteins and age-related functional decline. We studied plasma and skeletal muscle (SkM) HSP70 levels in adult vervet monkeys (life span ≈ 25 years) at baseline and after 4 years (≈10 human years). Insulin, glucose, homeostasis model assessment scores, triglycerides, high-density lipoprotein and total plasma cholesterol, body weight, body mass index, and waist circumference were measured repeatedly, with change over time estimated by individual regression slopes.

Low baseline SkM HSP70 was a proximal marker for developing insulin resistance and was seen in monkeys whose insulin and homeostasis model assessment increased more rapidly over time. Changes in SkM HSP70 inversely correlated with insulin and homeostasis model assessment trajectories such that a positive change in SkM level was beneficial. The strength of the relationship between changes in SkM HSP70 and insulin remained unchanged after adjustment for all covariates. Younger monkeys drove these relationships, with HSP70 alone being predictive of insulin changes with aging.

Results from aged humans confirmed this positive association of plasma HSP70 and insulin. In conclusion, higher levels of SkM HSP70 protect against insulin resistance development during healthy aging.

One possible explanation is that this measure, by focusing on a repair and maintenance marker, is a filter for the proportion of insulin resistance caused by low-level biological damage over time, rather than by lifestyle choices. Another possible explanation is that higher levels of HSP70 associate with more physical activity, and in turn with all of the benefits that this brings. So the study could be demonstrating an inverse measure of variations in vervet indolence, which then translates over time to different health trajectories. It would be interesting to see a similar primate study of artificially increased levels of HSP70 - an expensive proposition in a world in which mouse studies can cost millions, and would therefore have to be driven by something more concrete than mere interest.

A herd of mitochondria exist in every cell, each with their own copies of mitochondrial DNA. Mitochondria replicate like bacteria, and mitochondrial dynamics are complex and reactive. So counting mitochondria, such as by measuring levels of mitochondrial DNA, doesn't necessarily tell us anything about cause and effect. If we see this measure declining with aging, but not in long-lived individuals, that really only says that we might want to look more closely at the role of mitochondria in aging. Long-lived individuals are long-lived precisely because they have less damage and fewer age-related changes in their biochemistry:

Mitochondrial DNA (mtDNA) content plays an important role in energy production and sustaining normal physiological function. A decline in the mtDNA content and subsequent dysfunction cause various senile diseases, with decreasing mtDNA content observed in the elderly individuals with age-related diseases. In contrast, the oldest old individuals, for example, centenarians, have a delayed or reduced prevalence of these diseases, suggesting centenarians may have a different pattern of the mtDNA content, enabling them to keep normal mitochondrial functions to help delay or escape senile diseases.

To test this hypothesis, a total of 961 subjects, consisting of 424 longevity subjects and 537 younger control subjects from Hainan and Sichuan provinces of China, were recruited for this study. The mtDNA content was found to be inversely associated with age among the age of group 40-70 years. Surprisingly, no reduction of mtDNA content was observed in nonagenarians and centenarians; instead, these oldest old showed a significant increase than the elderly people aged between 50 and 70 years. The results suggest the higher mtDNA content may convey a beneficial effect to the longevity of people through assuring sufficient energy supply.

Link: http://dx.doi.org/10.1016/j.neurobiolaging.2014.01.015

Researchers here demonstrate a way to restore old muscle stem cell populations to youthful levels of activity and tissue maintenance, and show that it produces benefits in old mice:

The researchers found that many muscle stem cells isolated from mice that were 2 years old, equivalent to about 80 years of human life, exhibited elevated levels of activity in a biological cascade called the p38 MAP kinase pathway. This pathway impedes the proliferation of the stem cells and encourages them to instead become non-stem, muscle progenitor cells. As a result, although many of the old stem cells divide in a dish, the resulting colonies are very small and do not contain many stem cells.

Using a drug to block this p38 MAP kinase pathway in old stem cells (while also growing them on a specialized matrix called hydrogel) allowed them to divide rapidly in the laboratory and make a large number of potent new stem cells that can robustly repair muscle damage. "Aging is a stochastic but cumulative process. We've now shown that muscle stem cells progressively lose their stem cell function during aging. This treatment does not turn the clock back on dysfunctional stem cells in the aged population. Rather, it stimulates stem cells from old muscle tissues that are still functional to begin dividing and self-renew."

The researchers found that, when transplanted back into the animal, the treated stem cells migrate to their natural niches and provide a long-lasting stem cell reserve to contribute to repeated demands for muscle repair. "We were able to show that transplantation of the old treated muscle stem cell population repaired the damage and restored strength to injured muscles of old mice. Two months after transplantation, these muscles exhibited forces equivalent to young, uninjured muscles. This was the most encouraging finding of all."

Link: http://med.stanford.edu/ism/2014/february/blau.html

Young researchers intern each year at the SENS Research Foundation, doing their part to help advance the state of the art closer towards working rejuvenation treatments. The Foundation exists not just to coordinate and fund cutting edge research today, but also to help build the research community of tomorrow. Completing clinical deployment of the first generation of applied rejuvenation biotechnologies will be a big job, something that ideally will see the growth of a research community to rival the stem cell and cancer institutions in size, funding, and enthusiasm. Among today's life science undergraduates and graduates are those who will be leading laboratories two decades from now, creating therapies to reverse some of the causes of aging. But they haven't yet chosen that path, or made the necessary connections, or decided that they find the molecular biology of aging to be an exciting field, wide open for ambitious newcomers to make a mark.

If you look back in the Fight Aging! archives you'll find a few posts covering the SENS Research Foundation publications on their intern program:

• A Spotlight on SENS Research Foundation Interns
• Reviewing the Work of More of the SENS Research Foundation 2013 Interns
• Another Spotlight on SENS Research Foundation Interns

This is another post in the series, looking at the more of the work accomplished by last year's class. A number of articles have been published over the last month by the Foundation, and here they are:

Search begins for non-toxic enzymatic solution to macular degeneration: 2013 intern Anuj Kudva

Age-related macular degeneration (AMD) is a major cause of sight loss in the elderly. There are multiple risk factors that can result in the onset of AMD, but it is believed that the pathogenesis of AMD is due to dysfunctional retinal pigment epithelium (RPE) cells. It is believed that the buildup of a lipofuscin molecule called A2E within RPE lysosomes hinders the metabolic behavior of RPE cells and hence causes the AMD pathogenesis. Fortunately, a recent study has provided evidence that peroxidase enzymes can metabolize A2E within lysosomes. Unfortunately 10% of the cells died as a result of the enzymatic reaction.

The goal of my research team is to identify a peroxidase enzyme that can degrade the buildup of A2E with limited toxic side effects. My project focused on developing an assay to assess the cytotoxicity of possible peroxidase enzyme treatments. We decided to measure apoptosis as a readout of cytotoxicity. I tested a number of DNA damaging agents to establish a positive control for apoptosis. With a positive control established, I began Western blot analysis of the lysate from cells treated with or without a candidate peroxidase enzyme called SENS20. I found that SENS20 has no toxic effects at concentrations up to 100 ug. Once the team overcomes a few remaining technical issues, the assay will be ready for routine use. The apoptosis assay paves the way for more conclusive cytotoxicity studies in the future.

Generation of thymus ex vivo - SRF and WFIRM intern Daniel Bullock

The thymus is an essential component of the immune system, which configures T-cells to meet novel threats. Unlike most organs, the thymus reaches its maximum size and functionality around the onset of puberty after which it atrophies, leading to a decline in the immune system's ability to respond to new threats. If it were possible to prolong the viability of the thymus, or even revitalize it later in life, we might be able to bolster the body's defences against threats such as viruses, autoimmune diseases, and even cancer.

Our goal was to develop a method for growing a transplantable thymus, using donor thymus cells to colonize a scaffold containing an extracellular matrix, the mesh of tissue components found between cells. This entailed a number of intermediary steps, including harvesting thymic tissue from porcine donors, the decellularization of those tissues (i.e. reducing the tissue to an extracellular matrix), the harvesting of epithelial cells from murine donors, and finally the culturing of potential donor thymus tissue. Although these procedures have been successfully implemented in the past for a number of other organs and tissues, the precise protocols are only partly applicable for work with the thymus. Thus, a new protocol needed to be developed and optimized.

I performed a number of quantitative assessments to measure the optimization of the decellularization process and growth of thymic epithelial cell populations in vitro. Additionally, I also characterized the microphysical and biological features of the newly decellularized material. Our initial results have been promising and, as my internship was coming to a close, the lab was preparing to begin transplantation experiments in a live mouse model.

Stem cell-based therapy for the treatment of inflammatory bowel disease (IBD) - SRF intern John Moon

Inflammatory bowel disease is characterized by intestinal inflammation, which causes severe damage to the tissue of the intestinal lining. The precise cause of IBD remains uncertain. However, evidence suggests that dysregulation of the immune system plays a role in the autoimmune response that leads to the inflammation that characterizes IBD.

Mesenchymal stromal cells (or MSCs) are cells which differentiate into multiple tissue types and have been shown to reduce local inflammation, decrease the immune response, and counteract the signals released to recruit immune cells to the site of inflammation. It was therefore hypothesized that MSCs may be an effective therapy for IBD. However, clinical trials have demonstrated that MSC infusions were only effective in 30% of IBD patients. Furthermore, animal model studies have demonstrated that the limited tendency of MSCs to graft to the intestine may have been the limiting factor.

Previous work by the Almeida-Porada lab indicates that endothelial progenitor cells home promptly to the intestine. Therefore, my summer project sought to explore whether a cell-based therapy using a combination of both MSCs and endothelial cells (EC) would be an effective treatment for IBD.

Therefore, I isolated and characterized mesenchymal stromal cells and endothelial cells from human umbilical cord tissue. Then, I utilized flow cytometry and immunofluorescent double-staining to characterize these cells, and show that our cells are expressing molecules necessary for homing and immunomodulation. These results also lay the groundwork for future experiments to evaluate the effectiveness of cord tissue-derived MSC and EC cell therapy.

The lung is a very complex organ, and that complexity is one reason why the tissue engineering of lungs is lagging behind that of other, less complex organs. It will be a while yet before any organ can be reliably grown from the starting point of a patient's own cells - though groups like the New Organ initiative hope to speed the arrival of that goal.

There is a technology to bridge the gap between the donor transplants of today and the organs grown to order of tomorrow, however: it is decellularization. A donor organ can be stripped of its cells, leaving only the structure of the extracellular matrix. When new cells are introduced, such as those derived from a recipient's stem cells, they are guided by the scaffold and chemical cues of the extracellular matrix to reassemble the correct tissues. The end result is an organ that will match the patient with little to no threat of immune of rejection. It will even possible to use organs from pigs or other similarly sized animals to create a source of decellularized tissues for transplantation.

A few years ago researchers demonstrated the ability to create and transplant decellularized rat lungs. Here this popular science article notes that decellularization in human lungs has reached the proof of concept stage. It is interesting to see that researchers are far more ready to put timelines for development on the table than they were in past years:

For the first time, scientists have created human lungs in a lab -- an exciting step forward in regenerative medicine, but an advance that likely won't help patients for many years. "It's so darn cool," said Joan Nichols, a researcher at the University of Texas Medical Branch. "It's been science fiction and we're moving into science fact."

The researchers started with lungs from two children who'd died from trauma, most likely a car accident. Their lungs were too damaged to be used for transplantation, but they did have some healthy tissue. They took one of the lungs and stripped away nearly everything, leaving a scaffolding of collagen and elastin.

The scientists then took cells from the other lung and put them on the scaffolding. They immersed the structure in a large chamber filled with a liquid "resembling Kool-Aid" which provided nutrients for the cells to grow. After about four weeks, an engineered human lung emerged. Repeating the process, they created another lung from two other children who'd died.

The lab-made lungs look very much like the real thing, just pinker, softer and less dense. Nichols said she thinks it will be another 12 years or so until they'll be ready to try using these lungs for transplants. "My students will be doing the work when I'm old and retired and can't hold a pipette anymore." Before researchers experiment on humans, they'll try out lab-made lungs on pigs.

Link: http://www.wsbt.com/news/health/Human-lung-made-in-lab-for-first-time/24491024

The failing immune system of the elderly is characterized by a greatly increased number of memory T cells, and too few naive T cells capable of taking on new threats. One explanation for why this is the case is exposure to cytomegalovirus (CMV), a ubiquitous herpesvirus that the immune system cannot clear. Ever more T cells become uselessly devoted to fighting it until the immune system can no longer do its job. There are research results from human studies to support this view. It isn't the only reason that the immune system fails, but it may be one of the more important ones.

These researchers see a different picture when working in mice, however. To their eyes memory T cells are expanding in number with age due to some other process, something yet to be fully understood. CMV may prove to be a red herring yet, or this may turn out to be a significant difference between the immunology of mice and people:

The number of memory phenotype CD8 T cells increases dramatically with aging in both humans and mice. However, the mechanism for this is unknown. The prevailing hypothesis is that memory T cells accumulate with aging as a result of lifelong antigenic stimulation. However, data supporting this supposition are lacking.

In this study, we demonstrate that central memory CD8 T cells, which represent a large majority of memory CD8 T cells in aged mice, are not memory cells that develop in response to antigenic stimulation but are virtual memory cells that develop without antigenic stimulation. In addition to phenotypic evidence, we show that accumulation of central memory CD8 T cells is independent of CD4 T cells, CCR5, and CXCR3, all of which are known to be essential for [antigen]-driven development of central memory CD8 T cells. Thus, this study reveals a novel mechanism for aging-related changes in CD8 T cells.

The direct short-cut approach here is to destroy all these memory cells, and let the immune system repopulate with fresh new cells, perhaps helping it along with an infusion of cells generated from the patient's own stem cells. It doesn't matter how memory cells come to use up the allotted space for immune cells so long as they can reliably be singled out and cleared away.

Link: http://dx.doi.org/10.4049/jimmunol.1302509

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

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

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

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

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

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

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

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

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

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

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

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

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

Link: http://joshmitteldorf.scienceblog.com/2014/02/10/a-heavy-hitter-weighs-in-against-evolutionary-theory/

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

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

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

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

Link: http://dx.doi.org/10.1186/1742-4933-11-2

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

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

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

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

Geriatric muscle stem cells switch reversible quiescence into senescence

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

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

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

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

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

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

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

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

Link: http://childrensnational.org/pressroom/NewsReleases/study-identifies-protein-to-repair-brain-tissue-in-MS.aspx

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

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

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

Link: http://dx.doi.org/10.1038/ejhg.2013.299

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

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

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

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

Lifespan predicted from flashes in worm cells

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

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

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

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

Mitoflash frequency in early adulthood predicts lifespan in Caenorhabditis elegans

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

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

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

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

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

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

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

Link: http://uthscsa.edu/hscnews/singleformat2.asp?newID=4713

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

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

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

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

Link: http://dx.doi.org/10.1371/journal.pgen.1003974

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

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

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

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

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

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

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

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

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

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

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

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

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

Link: http://www.huffingtonpost.com/john-n-gray/john-gray-life-extension-_b_4732054.html

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

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

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

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

Link: http://dx.doi.org/10.1371/journal.pone.0088071

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

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

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

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

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

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

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

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

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

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

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

Link: http://www.impactaging.com/papers/v6/n2/full/100636.html

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

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

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

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

Link: http://www.impactaging.com/papers/v6/n1/full/100630.html

The nature of neural networks is perhaps better understood by more people nowadays than used to the be the case. Forms of neural network are used for a range of computational purposes, where they have proved useful as a way to economically discover solutions to difficult problems in pattern recognition, optimization, and other fields. How a particular solution works isn't always clear, especially when using larger networks, but if it can be proven to work well then why worry?

We ourselves are neural networks: the complex adaptive phenomena that we choose to call the self arises from comparatively simple exchanges between many, many neurons. The machine is the connections and the state of its neurons, constantly altering itself in response to circumstances and its own operation.

The brain, like all tissues, suffers due to the accumulation of cellular and molecular damage that drives aging. But which of the characteristic differences between a young brain and an old brain are aging, and which are the expected operation of the neural network as it processes and reprocesses the data gathered throughout life? In some cases the classification is obvious: broken blood vessels and white matter hyperintensities are damage, as is the amyloid that accumulates in Alzheimer's disease. We would be better off without them, and they harm us by destroying physical structures needed for operation of the brain. Once researchers start looking at the structure of neural connections, or activity in response to stimulus, or gene expression maps in various portions of the brain things become a little less clear, however:

The Brain Ages Optimally to Model Its Environment: Evidence from Sensory Learning over the Adult Lifespan

The aging brain shows a progressive loss of neuropil, which is accompanied by subtle changes in neuronal plasticity, sensory learning and memory. Neurophysiologically, aging attenuates evoked responses - including the mismatch negativity (MMN). This is accompanied by a shift in cortical responsivity from sensory (posterior) regions to executive (anterior) regions, which has been interpreted as a compensatory response for cognitive decline.

Theoretical neurobiology offers a simpler explanation for all of these effects - from a Bayesian perspective, as the brain is progressively optimized to model its world, its complexity will decrease. A corollary of this complexity reduction is an attenuation of Bayesian updating or sensory learning.

Here we confirmed this hypothesis using magnetoencephalographic recordings of the mismatch negativity elicited in a large cohort of human subjects, in their third to ninth decade. Employing dynamic causal modeling to assay the synaptic mechanisms underlying these non-invasive recordings, we found a selective age-related attenuation of synaptic connectivity changes that underpin rapid sensory learning. In contrast, baseline synaptic connectivity strengths were consistently strong over the decades. Our findings suggest that the lifetime accrual of sensory experience optimizes functional brain architectures to enable efficient and generalizable predictions of the world.

My suspicion is that it would be faster to implement rejuvenation biotechnologies and then assess what happens to an aging brain that remains physiologically young than to fully pick apart and understand present contributions to changes over time in the brain.

This line of research is of interest because of a potential threat to extreme longevity, past the present limits of human life span, once we have build the necessary medical technologies. The threat is this: it is possible that the brain is like the immune system, in that it is poorly structured for long term use, and will fail for reasons inherent to that structure, even in the absence of damage. We have no reason to suspect that this is the case, but equally there is no good reason to rule this out - the scientific community simply doesn't understand enough about the detailed operation of the brain to say either way with confidence.

On the plus side, this is a comparatively remote potential threat, something that lies decades past all the other fatal forms of damage and age-related disease that we have to deal with. Old people with little physical damage to their brains are sharp and on the ball, to the degree allowed by their failing bodies and decades of increasing caution required in their interaction with the world. Further, by the time we are at the point of worrying about this, biotechnology will be far more advanced. So it is, I think, worth considering, but not worth panicking over.

Species that experience greater levels of predation should not tend to evolve greater longevity, or so the established theory goes. There is debate on this topic, however, as in all areas where researchers must rely as much on models and inference as on data. Here is an example of the sort of modeling work that takes place in this field:

The evolutionary theories of aging are useful for gaining insights into the complex mechanisms underlying senescence. Classical theories argue that high levels of extrinsic mortality should select for the evolution of shorter lifespans and earlier peak fertility. Non-classical theories, in contrast, posit that an increase in extrinsic mortality could select for the evolution of longer lifespans. Although numerous studies support the classical paradigm, recent data challenge classical predictions, finding that high extrinsic mortality can select for the evolution of longer lifespans.

To further elucidate the role of extrinsic mortality in the evolution of aging, we implemented a stochastic, agent-based, computational model. We used a simulated annealing optimization approach to predict which model parameters predispose populations to evolve longer or shorter lifespans in response to increased levels of predation. We report that longer lifespans evolved in the presence of rising predation if the cost of mating is relatively high and if energy is available in excess. Conversely, we found that dramatically shorter lifespans evolved when mating costs were relatively low and food was relatively scarce.

We also analyzed the effects of increased predation on various parameters related to density dependence and energy allocation. Longer and shorter lifespans were accompanied by increased and decreased investments of energy into somatic maintenance, respectively. Similarly, earlier and later maturation ages were accompanied by increased and decreased energetic investments into early fecundity, respectively. Higher predation significantly decreased the total population size, enlarged the shared resource pool, and redistributed energy reserves for mature individuals. These results both corroborate and refine classical predictions, demonstrating a population-level trade-off between longevity and fecundity and identifying conditions that produce both classical and non-classical lifespan effects.

Link: http://dx.doi.org/10.1371/journal.pone.0086602

AgeFactDB is an abstraction layer built on top of other published databases relevant to aging. One of the benefits of open access science is that people can far more easily work on better ways to present and analyze research results: it enables a faster process of evolution towards ever more useful tools. In this the scientific community is catching up but still years behind the open source software world, held back by a culture of restricted access to information that has only comparatively recently started to give way to the much more sensible ideal of open access.

The JenAge Ageing Factor Database AgeFactDB is aimed at the collection and integration of ageing-related data. In a first step it combines data from existing databases with age-related information, such as the Lifespan Observations Database and the GenAge Database. Information from further data sources will be included step by step. Value will be added to these data in several ways. One example is the consistent usage of synonyms for gene and protein names. In addition, new ageing-related information will be included both by manual and automatic information extraction from the scientific literature.

Ageing factors include genes, chemical compounds and other factors such as dietary restriction or overfeeding, heat shock, low temperature and so on whose action results in a changed lifespan or another ageing phenotype. Information related to the effect of ageing factors on life span and/or ageing phenotype is called an observation and is presented in the database on observation pages. To provide an easy and compact access to the complete information for a particular gene or a specific compound or for one of the other factors the corresponding observations are also summarised on ageing factor pages.

Based on a comprehensive homology analysis, AgeFactDB provides, in addition to known ageing-related genes, a compilation of genes that are homologous to these known genes. These homologs can be considered as candidate or putative ageing-related genes.

Link: http://agefactdb.jenage.de/

Earlier this week I pointed out the first part of a three part series by Eric Schulke of the Movement for Indefinite Life Extension. Taken as a whole it's a point by point examination and defense of SENS, the Strategies for Engineered Negligible Senescence, as the best path forward towards extending human life. Moreover it is a defense of getting up and actually doing something about degenerative aging - and these days that has more need of defense than the viability of rejuvenation research after the SENS model.

We live in a bizarre mirror world in which the populace sleepwalk towards decrepitude and death, and in which the vast majority of the public have no interest in supporting efforts to extend healthy life spans. Instead they lavish their attention and dollars on fake "anti-aging" products, ways to create a pretense of youth, while talking heads tell us how terrible it would be if we actually lived longer. Yet at the same time the possibility of actually treating and reversing degenerative aging is right there in front of us, a realistic near-term goal for the research community. Further, we already live longer, on average, than our ancestors, and life expectancy for adults has slowly risen for more than a century - something taken for granted and then forgotten. It's a madhouse.

I like to see enthusiasm for longevity science of the sort exhibited in the articles quoted below: people have to speak out to illustrate the madness of the common culture and the importance of work on human rejuvenation therapies. It is helpful and encouraging that sentiments of this nature continue to emerge from the community. This is what is needed to move the needle, to continue the progress in research and advocacy that in the past decade or two has brought us from nothing to the point at which we can talk at all about SENS and tangible progress towards rejuvenation of the old.

Defeating aging, and the avenues ahead of us: Part 1

"[...] the most promising ways to postpone aging are by disrupting the pathways underlying it, just as we do for specific diseases." That line sums up an important element of strategies for engineering negligible senescence (SENS) in Aubrey de Grey's book Ending Aging, published in 2007. The book outlines the straightforward sense in disrupting the pathways that cause us to age: by engineering the damage of aging out of our biology after the body has experienced the damage, but before the damage accumulates to deadly levels.

Defeating aging, and the avenues ahead of us: Part 2

There seem to be only those seven forms of damage that age us to death by accumulating in and around our cells. These forms of damage have been discovered by science over the years, the last one being found in the 1980s. It's not "seven plus all the ones we can't get a grip on or figure out yet." It's not "seven just because these are Aubrey's or some group's favorite seven", and it's not "seven but we have absolutely no idea how we could even begin to think about tackling any of them." This isn't a widely disputed list of items. It has accumulated and been independently peer-reviewed through all of science over time.

As written in Ending Aging, "You could stop thinking of aging as a hopelessly complex theoretical problem to solve, and get on with attacking it head-on, as an engineering challenge that needed to be overcome." You can, and you must. At the very least, this engineering approach is one of the main avenues that needs full support of as many people from around the world as possible, and as soon as possible.

Defeating aging, and the avenues ahead of us: Part 3

Act like you've seen the growing graveyards in your area, and face the reality that you, too, will be dead soon if the world, which includes you, doesn't rise to the challenge and do something about it.

Almost everything you do can and should involve this cause. Going on vacation? Bring some books or literature about this to give away. Socializing? Talk to them about it a bit and hang out with the ones that are amicable to this cause when you can. Going on the Internet? Be sure to share or comment on a related topic or three when you can. Looking for a career to get into or ways to spend your free time? Get involved with this cause. I and the people I know do these things and more.

Pick up the proverbial shovel and help with SENS. Help spread awareness, bring more people into the related conferences, write books, work with the media, talk to politicians, etc. Go into research if you have the aptitude for it. You can pick any lead that you find to be viable. Research existing methods to combat the damage, create your own methods, or do an exhaustive study to try to make the case for forms of damage in addition to the seven generally accepted types. Get in where you fit in.

If you need help with it, then ask in just about any of the communities involved in this. Help us get these mountains moved. Through exhausting more and more avenues and pathways, the picture will continue getting clearer. Answers to achieving negligible senescence and extending our happy, healthy life spans, will materialize. There is no "well, it can't work", "they aren't sure if we should yet", "it's too speculative", etc. It's not. We are dying, we have options, we get moving.

From my perspective the balance of evidence suggests that the progressive shortening of average telomere length with advancing age is a marker of damage and dysfunction, not a primary form of damage in and of itself. That telomerase gene therapy has lengthened life span in mice means that reseachers should focus on how this might be happening rather than assuming it is because of telomere lengthening: for one thing telomerase has many functions, not all of which are at all well understood, and for another mouse telomere dynamics are quite different from those of humans.

Nonetheless, there are plenty of folk who think that we should focus on telomere lengthening, such as this advocate who holds to the programmed view of aging:

You would think that the 2009 Nobel Prize might have done more to raise the profile of research in telomere biology, but the field remains a specialized backwater of medical research, and few biologists (fewer doctors) take it seriously as a panacea for the diseases of old age. If the National Institutes of Health have money to put into heart disease and cancer and Alzheimer's and Parkinson's diseases, there is no better place to invest than in telomere biology. Research on these diseases commands multi-billion dollar budgets, because they are considered "medicine", funded by NIH, while telomere biology is considered "science" and is funded by NSF. The total NSF budget for all cell biology is only $123 million, and the portion devoted to telomere biology is a few million. The private sector is doing a little better - there are several companies selling herbs that stimulate our own bodies to liberate telomerase. But this is short-sighted venture capital, and what we need is focused research with a ten-year vision.

There is good reason to think that telomere length is a primary aging clock in the human body. The body knows perfectly well how to lengthen telomeres, but chooses not to. All we have to do is to signal the body to activate the telomerase genes that are already present in every cell. Of course, there is no guarantee that this will work, but compared to the sluggish rate of progress on individual diseases, it's a pretty good bet, and the target is rather simple. IMHO, it's worth a crash research effort.

Link: http://joshmitteldorf.scienceblog.com/2014/01/25/the-most-promising-medical-technology-on-the-horizon-today/

A number of studies show that general antioxidant supplementation interferes with beneficial processes, and is thus harmful to long term health. This post references some of the more recent research on this topic:

You may remember a study that suggested that antioxidant supplement actually negated the effects of exercise in muscle tissue. (The reactive oxygen species generated are apparently being used by the cells as a signaling mechanism, one that you don't necessarily want to turn off). That was followed by another paper that showed that cells that should be undergoing apoptosis (programmed cell death) could be kept alive by antioxidant treatment. Some might read that and not realize what a bad idea that is - having cells that ignore apoptosis signals is believed to be a common feature in carcinogenesis, and it's not something that you want to promote lightly.

Here are two recent publications that back up these conclusions. The BBC reports on this paper from the Journal of Physiology. It looks like a well-run trial demonstrating that antioxidant therapy (Vitamin C and Vitamin E) does indeed keep muscles from showing adaptation to endurance training. The vitamin-supplemented group reached the same performance levels as the placebo group over the 11-week program, but on a cellular level, they did not show the (beneficial) changes in mitochondria, etc.

Then there's this report in The Scientist, covering this paper in Science Translational Medicine. The title says it all: "Antioxidants Accelerate Lung Cancer Progression in Mice". In this case, it looks like reactive oxygen species should normally be activating p53, but taking antioxidants disrupts this signaling and allows early-stage tumor cells (before their p53 mutates) to grow much more quickly.

This is all rather frustrating when you consider the nonstop advertising for antioxidant supplements and foods, especially for any role in preventing cancer. It looks more and more as if high levels of extra antioxidants [at] the very least help along any cancerous cells that might arise on their own. Evidence for this has been piling up for years now from multiple sources, but if you wander through a grocery or drug store, you'd never have the faintest idea that there could be anything wrong with scarfing up all the antioxidants you possibly can.

Link: http://pipeline.corante.com/archives/2014/02/05/the_evidence_piles_up_antioxidant_supplements_are_bad_for_you.php

One of the fundamental ways in which old tissue is different from young tissue is the presence of deposits of misfolded proteins between cells. In their normal form these proteins should remain dissolved in tissue fluids, but with age ever more precipitate to form the strands and fibrils known as amyloid. There are a number of different types of amyloid, each corresponding to a particular protein that is prone to this outcome. For many of these types the research community cannot yet explain exactly why and how the amyloid contributes to the age-related conditions it is associated with, or indeed why and how this is an age-related phenomenon. Is it a failure in clearance mechanisms caused by other forms of damage, perhaps? For some forms of amyloid a great deal is known, however: take Alzheimer's disease, for example. If the average fellow in the street has heard of amyloid at all, it is probably in connection with Alzheimer's research and the present focus of treatment.

There is another arguably equally important condition and form of amyloid, one that appears to act as a limiting factor on human life span, and receives far less attention and funding than does Alzheimer's disease. The results of autopsies performed on supercentenarians, people who lived to be 110 years of age or older, suggest that those of us who survive or evade every other potential fatal age-related condition are eventually felled by the buildup of transthyretin amyloid, leading to a condition known as TTR amyloidosis, or senile systemic amyloidosis when referring to the age-related condition rather than the genetic disease that can cause similar early-life buildup of amyloid.

Since there is all too little work taking place on senile system amyloidosis, this is one of the areas in which the SENS Research Foundation has stepped into accelerate matters in the past couple of years. One of the key insights that led to the existence of the Foundation is that we don't in fact have to have a complete understanding of the mechanisms involved in any particular cause of aging to effectively treat it. What we do need is a comprehensive list of differences between old tissue and young tissue, a good identification of which of those differences are fundamental - primary causes versus secondary effects - and a plan to reverse those differences.

In the case of amyloids we have all of these items: it doesn't matter that researchers cannot yet explain how and why some forms of amyloid cause harm if the development community can build the means to remove these amyloids. We should just remove them, as they are not a feature of young tissue. Much of the work of the Alzheimer's research community, for example, will hopefully be broadly applicable to forms of amyloid other than that associated with the condition. Progress by Alzheimer's researchers towards immune therapies that can attack and break down amyloid is watched with interest in a number of other fields.

Here is a piece by Jason Hope, a philanthropist who has contributed meaningfully to some of the SENS Research Foundation programs:

Fight Aging  -  Extracellular Aggregates

Aggregation of one specific protein causes problems in many parts of body but inflicts special harm to the heart in particular. Transthyretin, or TTR, is a transporter protein that carries thyroid hormones to the various parts of the body that need it. By the time they reach the age of 70 years, 10 percent of people suffer significant accumulations of TTR amyloids. The condition becomes nearly universal as people reach the century mark. TTR amyloid may prevent a body from reaching its destiny as a "supercentenarian" who lives more than 110 years.

To date, there is no approved treatment for amyloids aside from organ transplant to replace organs damaged by amyloids. The SENS Research Foundation-funded TTR Extracellular Aggregates collaboration is working to develop antibodies that identify and safely remove TTR amyloid deposits from body tissues. The antibodies do this by binding to TTR. Physicians could someday use these antibodies to diagnose and treat both age-induced and genetic forms of TTR.

To create these antibodies, Dr. Brian O'Nuallain and his collaborators immunized three strains of mice with three different TTR-containing substances intended to provoke an immune response. Exposure to these substances triggered an immune response in the mice  -  each group of mice created unique antibodies that would target different types of aggregating TTR. This means the scientists created antibodies already armed to fight only clumping TTR, ignoring any TTR remaining in a form that can remain dissolved in body fluids. Seven of these antibodies show diagnostic and therapeutic potential. All seven bind strongly to clumped TTR and ignore soluble TTR well. O'Nuallain is collaborating with Dr. Sudhir Paul to learn if these antibodies can facilitate the breakdown of TTR amyloids.

Dr. Paul works on developing catalytic antibodies, known as catabodies for short, which break down TTR amyloids. Catabodies do not just bind to TTR amyloids and carry them away  -  catabodies destroy TTR amyloids. In earlier research, Dr. Paul identified naturally occurring catabodies that break down TTR amyloids found in the brains of patients with Alzheimer's disease. Today, with funding from SENS Research Foundation, he has identified catabodies that completely dissolve TTR amyloids in a test tube without damaging TTR proteins that are functioning correctly.

This is important work on the foundations of human rejuvenation, and I look forward to hearing of further advances towards clinical application. Given the present structure of medical regulation that will probably involve development of a treatment of the genetic version of TTR amyloidosis however - it remains the case that regulators at the FDA do not recognize aging as a condition to be treated, and there is thus no path to approval for treatments for aging. This roadblock echoes all the way back down the research and development pipeline, which goes some way towards explaining why there is still comparatively little funding for work on amyloidosis and other necessary portions of a rejuvenation toolkit.

That said, it is good to see progress in the laboratory towards targeted and focused methods of designing treatments: attack the problem molecule and only the problem molecule. We live in an age of biotechnology, and ongoing work should absolutely be far above and beyond the old school drug development programs in which compounds from the natural world are thrown at the problem until something is found that causes more good than harm. Sadly there is still all too much of that going on today.

In its role as an adaptation to suppress cancer, it makes sense that cellular senescence can to some degree spread through a cell population, as well as alter the behavior of surrounding cells in other ways. After all if one cell in a tissue is at risk of cancer, then it is likely others will also be under threat. So the more senescent cells there are, there more likely it is that nearby cells will also become senescent. This is driven by what is called senescence-associated secretory phenotype (SASP) - the particular combination of signaling and other proteins emitted by senescent cells.

This would all be fine and well, but the presence of senescent cells harms tissue integrity and causes other forms of dysfunction that contribute to the advance of degenerative aging. The immune system does work to destroy these cells, but falls down badly on that job in later life: senescent cells accumulate and cause great harm. Ideally we'd want to destroy them all and management of cancer suppression and treatment through medical technology, thus having the best of both worlds. This approach lies near in the future: almost all of the necessary pieces already exist, and it is just a matter of marrying some form of targeted cell destruction technology of the sort developed for use as a cancer therapy with some way of reliably detecting senescent cells based on their distinctive biochemistry.

Here researchers are looking at SASP in more detail, to see how it impacts the ability of one stem cell population to do its job of tissue maintenance:

Cellular senescence is the permanent arrest of cell cycle, physiologically related to aging and aging-associated diseases. Senescence is also recognized as a mechanism for limiting the regenerative potential of stem cells and to protect cells from cancer development. The senescence program is realized through autocrine/paracrine pathways based on the activation of a peculiar senescence-associated secretory phenotype (SASP).

We show here that conditioned media (CM) of senescent mesenchymal stem cells (MSCs) contain a set of secreted factors that are able to induce a full senescence response in young cells. To delineate a hallmark of stem cells SASP, we have characterized the factors secreted by senescent MSC identifying insulin-like growth factor binding proteins 4 and 7 (IGFBP4 and IGFBP7) as key components needed for triggering senescence in young MSC.

These results suggest the occurrence of novel-secreted factors regulating MSC cellular senescence of potential importance for regenerative medicine and cancer therapy. [We] believe that our results pave the way to further investigations aiming to modify, in the near future, the current in vitro MSC expansion protocols for therapeutic purposes, thereby preventing or reducing the occurrence of negative senescence-related effects, and to better understand the complex process of senescence and aging in stem cells.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847322/

One contributing cause of age-related immune system dysfunction is exposure to cytomegalovirus (CMV). Near everyone has it by the time they reach old age, and this persistent herpesvirus coerces ever more of the immune system's limited resources to uselessly battling it - the body cannot effectively clear CMV, but it continues to try, year after year. Immune cells that should be undertaking other, far more vital work are sidelined into the dedicated watch for CMV.

The best short term approach to this problem may be to adapt targeted cell-killing technologies developed for use against cancer and adapt them to destroy CMV-specific immune cells, based on targeting the distinctive surface chemistry of these cells. That would free up immune system capacity for more useful cells to emerge.

This study identified a novel, striking link between CMV-specific cellular immunity and vascular changes in older life. The vast majority of CMV-infected people had CMV-specific CD4+ T cells in their peripheral blood that displayed the hallmarks of iTregs and whose frequency was significantly associated with both mean arterial blood pressure and diastolic blood pressure in a linear regression model. The frequencies of CMV-specific CD8+ effector T cells were highly correlated with these regulatory-type CD4+ T cells and, likewise, significantly associated with mean arterial blood pressure and diastolic blood pressure. These observations point to a direct link between quantitative measurements of CMV-specific immunity and functional vascular parameters. These findings were not explained by confounders such as age, inflammation (ie, CRP level), BMI, smoking history, or use of antihypertensive medication.

In conclusion, our study provides new and compelling evidence of a quantitative link between CMV-specific cellular immunity and blood pressure or, indirectly, vascular stiffness in older age. Together, these findings may indicate that CMV has an important role in driving vascular changes in older life that ultimately affect survival. The level of cellular immunity to CMV might become an important target for intervention in the future, because it is doubtful that the huge CMV-specific T-cell expansions observed in some CMV-infected people are actually required to control infection.

Link: http://jid.oxfordjournals.org/content/early/2013/12/09/infdis.jit576.long

A biological mechanism might be important in aging if it is comparatively easy to produce good correlations between measures of the progression of that mechanism and mortality rates. The effects of minor contributions to aging can be swamped when looking at human data, since you can't carefully construct your study populations and follow them for their entire lives - it is hard to pick out small effects using statistical analysis of general study data. But if every study group consistently shows strong associations for the measure at hand, then that is a sign that there is something worth looking into there.

It is well known that chronic inflammation is a bad sign when it comes to long-term health. On the one hand higher levels of constant inflammation are produced by conditions that are harmful in and of themselves, such as the functional decline of the immune system and an excess of visceral fat tissue and the lifestyle choices needed to produce it, and so on. On the other hand chronic inflammation is also harmful in and of itself, a dysfunction in the normal operation of metabolism and destructive to tissues, a process that contributes to the progression of numerous age-related conditions.

Here is an example that demonstrates how straightforward it is now to find good correlations between measure of inflammation and human mortality, and that these correlations are very consistent across study populations:

Simple Biologically Informed Inflammatory Index of Two Serum Cytokines Predicts 10 Year All-Cause Mortality in Older Adults

In total, 15 nuclear factor-kappa B-mediated pathway markers of inflammation were first measured in baseline serum samples of 1,155 older participants in the InCHIANTI population. Of these, C-reactive protein, interleukin-1-receptor antagonist, interleukin-6, interleukin-18, and soluble tumor necrosis factor-α receptor-1 were independent predictors of 5-year mortality. These five inflammatory markers were measured in baseline serum samples of 5,600 Cardiovascular Health Study participants. A weighted summary score, the first principal component summary score, and an inflammation index score were developed from these five log-transformed inflammatory markers, and their prediction of 10-year all-cause mortality was evaluated in Cardiovascular Health Study and then validated in InCHIANTI.

The inflammation index score that included interleukin-6 and soluble tumor necrosis factor-α receptor-1 was the best predictor of 10-year all-cause mortality in Cardiovascular Health Study, after adjusting for age, sex, education, race, smoking, and body mass index compared with all other single and combined measures. The inflammation index score was also the best predictor of mortality in the InCHIANTI validation study. Stratification by sex and [cardiovascular disease] status further strengthened the association of inflammation index score with mortality.

[Thus] a simple additive index of serum interleukin-6 and soluble tumor necrosis factor-α receptor-1 best captures the effect of chronic inflammation on mortality in older adults among the 15 biomarkers measured.

A great deal of chronic inflammation is self-inflicted in this age of low-cost and widely available calories. Eat to excess and become fat, and you pile an additional burden on yourself that will wear you down into age-related disease far earlier than your peers, all other things being equal. Even small amounts of excess visceral fat tissue held for years have a large impact on health in later life. Calorie restriction and regular exercise seem to be the optimal way to go when it comes to making the most of an imperfect biology.

As to the rest of it, the chronic inflammation that you cannot avoid because it stems from low-level biological damage to your immune system and tissues that happens to everyone, no matter how good your health, the best you can do today is to support the research that will lead to rejuvenation treatments tomorrow. Reverse the damage, restore the immune system, and that will remove the causes of chronic inflammation. That can't be done today, but it will be possible in the near future. Just how near depends on fundraising and advocacy here and now: new medicine doesn't just emerge from nothing.

A point is made here by Maria Konovalenko of the Science for Life Extension Foundation, who has been involved in the past couple of years of work on starting single issue longevity science political parties in Europe and Russia:

If a given idea has 20 million followers, it doesn't need a state to win. It has already won. It can form an alternative system of decision making on the Internet, i.e. create the crowd-power.

Radical life extension is the strongest idea in the history of mankind. The Pirate party and the Green party may serve as an example of how the international life extension party will be created. First of all, there has to be a circle of people who share the same value, and separate flamboyant actions that highlight this value. Just like Greenpeace performed this action when they sailed to the island where the nuclear testing was about to take place.

However we are aware that radical life extension idea still hasn't got enough followers, and public actions are needed to attract new supporters, because actionism is also quite fascinating. Maybe we should float 400 coffins into the Hudson River so that people will see with their own eyes how many people die in New York every day.

Another way of using the power of the crowd is crowdfunding of scientific experiments. And it's important to say that there are such experiments that possess the power of political acts, meaning they extend the limits of what's possible and set the direction of further movement.

Link: http://mariakonovalenko.wordpress.com/2014/02/02/life-extension-is-a-political-task/

One of the reasons that cancer is overwhelmingly a condition of the old is that the immune system is responsible for eliminating potentially cancerous cells, but declines in effectiveness with age due to a combination of damage and structural issues. The immune system supports a limited number of cells and continually devotes some of those cells to remembering threats - by late in a normal human life space it begins to experience resource issues, overburdened by memory cells and lacking enough naive cells to effectively tackle new threats.

Methods of even partially rejuvenating the immune system, such as implementing portions of the SENS program, or selectively destroying the burden of immune cells uselessly specialized to fight CMV so as to free up space for new and more useful immune cells to emerge, should reduce incidence of cancer in the old.

The research noted here illustrates this point, demonstrating just how important the immune system is to suppression of one particular type of cancer:

Immune cells undergo 'spontaneous' changes on a daily basis that could lead to cancers if not for the diligent surveillance of our immune system. This immune surveillance accounts for [the] 'surprising rarity' of B-cell lymphomas in the population, given how often these spontaneous changes occur.

The discovery provided an answer to why B-cell lymphomas occur in the population less frequently than expected. "Each and every one of us has spontaneous mutations in our immune B cells that occur as a result of their normal function. It is then somewhat of a paradox that B cell lymphoma is not more common in the population. "Our finding that immune surveillance by T cells enables early detection and elimination of these cancerous and pre-cancerous cells provides an answer to this puzzle, and proves that immune surveillance is essential to preventing the development of this blood cancer."

The research team made the discovery while investigating how B cells change when lymphoma develops. "As part of the research, we 'disabled' the T cells to suppress the immune system and, to our surprise, found that lymphoma developed in a matter of weeks, where it would normally take years. It seems that our immune system is better equipped than we imagined to identify and eliminate cancerous B cells, a process that is driven by the immune T cells in our body."

Link: http://www.eurekalert.org/pub_releases/2014-02/waeh-rab013014.php

Cancer is an age-related disease. It can happen at any age, but the odds are very low until you start into later life. There are many possible reasons as to why this is the case: the progressive decline in effectiveness of the immune system, which detects and destroys cancerous and potentially cancerous cells; rising levels of stochastic damage to nuclear DNA; greater inflammation and disarray in metabolism resulting from other forms of cellular and molecular damage associated with aging.

How about epigenetic changes, however? The number, type, and position of molecules attached to nuclear DNA continually alter in response to environment, health, and age. Much of this is presumably a response to the above noted damage and dysfunction, a reaction to circumstances. These decorating molecules act to alter gene expression, the rate at which proteins are produced from each blueprint gene, and thus alter the behavior of cells. Epigenetic patterns are different in every cell and tissue and between individuals, but characteristic differences between old people and young people can be discerned given enough data and computing power.

NIH Study Offers Insight into Why Cancer Incidence Increases with Age

Scientists have known for years that age is a leading risk factor for the development of many types of cancer, but why aging increases cancer risk remains unclear. Researchers suspect that DNA methylation, or the binding of chemical tags, called methyl groups, onto DNA, may be involved. Methyl groups activate or silence genes, by affecting interactions between DNA and the cell's protein-making machinery.

[Researchers] identified DNA methylation sites across the human genome that changed with age. They demonstrated that a subset of those sites - the ones that become increasingly methylated with advancing age - are also disproportionately methylated in a variety of human cancers. "You can think of methylation as dust settling on an unused switch, which then prevents the cell from turning on certain genes. If a cell can no longer turn on critical developmental programs, it might be easier for it to become a cancer cell."

You might recall that in recent years researchers have started to make inroads in using DNA methylation patterns as a measure of chronological and biological age. If that works - and it appears to - it shouldn't be surprising to also find associations with cancer.

I am far from the only person out there who sees the Strategies for Engineered Negligible Senescence (SENS) research programs as the best and most clear path to lengthening healthy human life spans - including our own, by reversing the course of aging should these new medical technologies be developed rapidly enough.

A great deal has changed over the past twenty years when it comes to the prospects for longevity-enhancing therapies. The topic wasn't even discussed openly in the mainstream research community back then, and to talk about extending life was a usually a quick ticket to losing your funding for the study of aging. Those days are gone, thankfully, due to a combination of activism and demonstrations of extended lifespans in a range of laboratory species.

Still, time is ticking, and it remains the case that there is no massive program underway to treat, prevent, and reverse human aging. SENS offers the possibility of rejuvenation biotechnologies arriving twenty years from the point at which it becomes that massive program, but as of today it is only funded with a few million dollars in philanthropic donations each year. That is more than zero, which is where we were ten years ago, but it is a long way from what is needed for best possible speed.

When I was in high school in the 1990s, as I recall, a segment of one of our classes focused on aging and lasted for a few weeks. Our teacher left us with the impression that aging was impossibly mysterious and probably always would be. He seemed to take a somber tone when talking about it. I wish I would have kept thinking about it then. I wish my science teacher, and science teachers around the world, had possessed more scientific and critical-thinking courage to instill more of a drive in us students to take the challenge on, daunting though they were convinced it was in those days.

[Over the past two decades] the reality of what humanity knows about aging and its surrounding issues has been changed through a multitude of scientific insights, from a variety of researchers and organizations around the world. The clearest of the ways forward, leading the charge, is the concept of eradicating the damage that is building up in our bodies and killing us, as outlined and taken on by SENS.

Regardless of which paths we take, one way or another we have to go through, around, over, under, or some other way to obviate the effects of this damage. And yes, we do have to do it. Life is far too mysterious and incredible to coddle the grave and yawn at the future. If there were semi-understandable reasons to excuse away potential paths and hypotheses to defeating aging in the 1990s and before, the first decade of the 21st century has been the herald of a new age in understanding of aging. It has been over a decade now since there was an excuse for teachers to discourage students from thinking about cures for aging. We can't accept procrastination as an answer.

Link: http://ieet.org/index.php/IEET/more/schulke20140201

A mini-review on the topic of cellular senescence, one of the contributing causes of degenerative aging:

Replicative cellular senescence was first described in cell culture as an irreversible growth arrest triggered by the accumulation of cell divisions in human fibroblasts. It has since been demonstrated in virtually all vertebrate species and cell types that have been examined. Telomere shortening due to replicative exhaustion was the first cause of senescence to be well understood. In the last decade, however, it has become evident that cellular senescence can be triggered by many intrinsic and extrinsic stimuli, including the activation of oncogenes, ionizing and ultraviolet irradiation, reactive oxygen species, pharmacological agents that modify DNA or chromatin, and even nutrient imbalances and ill-described cell culture stresses.

Recent data have implicated cellular senescence as an important in vivo tumor suppression mechanism. However, solid connections between cellular senescence and organismal aging have been slower to emerge. An important impediment has been the lack of reliable assays to distinguish senescent cells from the majority of healthy but quiescent cells found in normal tissues. While a few years ago it was questioned whether senescent cells existed in vivo in appreciable numbers, today it is increasingly evident that they accumulate with age as well as at sites of age-associated pathologies.

Implication of cellular senescence in stem cell aging has added renewed credence for its importance in species with considerable renewable tissues. Studies in mouse models lacking p16Ink4a-positive senescent cells, as a result of p16Ink4a gene inactivation or drug-induced cell clearance, have implied a causal link between senescence and age-related functional decline of tissues and organs. This together with the discovery that some of the major aging-related diseases are characterized by accumulation of senescent cells has raised the possibility that therapeutic removal of senescent cells may improve healthy lifespan.

Link: http://dx.doi.org/10.1186/2046-2395-2-7