Fight Aging! Newsletter, March 21st 2016

March 21st 2016

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

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  • Aubrey de Grey on Recent Progress and Future Economics in Rejuvenation Research
  • Reviewing the Mitochondrial Basis of Aging
  • An Attempt to Attenuate the Bad Behavior of Senescent Cells
  • Considering Genetic Variants and Superlongevity
  • Thinking About the Pipeline: Getting Therapies into Clinics
  • Latest Headlines from Fight Aging!
    • An Interview with the Major Mouse Testing Program Principals
    • Considering Mind Uploading as a Destination
    • Dysfunctional Energy Metabolism in Wet Macular Degeneration
    • Towards Self-Regulating Bioartifical Heart Patches
    • Increased NADPH Levels Extend Life in Female Mice Only
    • Progress Towards Recellularized Human Hearts
    • An Example of Failure to Replicate Associations Between Gene Variants and Longevity in Humans
    • Targeting Therapeutics to Cancer Cells Enhances Existing Chemotherapy While Cutting Side-Effects
    • Towards a Stem Cell Treatment for Osteoporosis
    • Regrowth of Dendritic Spines Recovers Memories Lost to Alzheimer's Disease Pathology


Today I'll point out a couple of recent technology press articles in which Aubrey de Grey of the SENS Research Foundation discusses recent progress and a few aspects of the expected near future of rejuvenation therapies. Money, as ever, occupies a large portion of the picture. Funding the right lines of research is critical to progress in medical technology, and the road towards human rejuvenation, towards creating the envisaged therapies capable of repairing the molecular damage that causes aging and age-related disease, is no exception to this rule. Funding, persuasion, public support, and public attention are all intertwined, however. The potential for meaningful progress towards rejuvenation therapies has existed since at least the 1990s, yet has only just started in earnest these past few years. Progress has been incremental and slow, the funding very thin on the ground. This is because little attention was given to aging research, and in a public space dominated by the flim-flam of the "anti-aging" industry, legitimate longevity science simply wasn't taken seriously. To bootstrap a new movement, which is exactly what has taken place for the SENS approach to rejuvenation research over the past decade, you really have to dig in to the ways in which persuasion, publicity, and the availability of funding all depend upon one another. There is a reason that bootstrapping is hard and takes time when starting out with little in the way of either support or resources.

The scientific and advocacy communities have come a long way since I started following the research and writing on the topic. It is easy to forget just how fringe was the idea of undertaking serious efforts to rejuvenate humans ten to fifteen years ago, and how much of a struggle it was to raise even a million in funding over a period of some years to get started on small scientific projects. For all that there remains a lot to accomplish and a long way to go yet towards the goal of the first comprehensive suite of rejuvenation treatments, it is tremendously empowering to see that all the past efforts - the years of hard work for few immediate gains at the outset of the bootstrapping process - have come to something. The wheel is turning and speeding, more people are joining the community and helping out, and there are actual SENS rejuvenation technologies in trials and startup companies, with the likelihood of more to come in the next few years. This is still only the beginning of the story. But for those of us who were striving to get the wheel to move at all some years ago, it is a rewarding time to be in the field.

Aubrey de Grey: Aging Research "Moves on Almost Every Week"

It's an exciting time to be working in ageing research. New findings are coming thick and fast, and although eliminating the process in humans is still some way away, studies regularly confirm what some have suspected for decades: that the mechanisms of ageing can be treated. "It's an amazingly gratifying field to be part of," says biomedical gerontologist Aubrey de Grey, chief science officer and founder of SENS Research Foundation, the leading organisation tackling ageing. "It moves on almost every week at the moment."

At the start of February, for example, a study was published that had hugely significant findings for the field. "There was a big announcement in Nature showing that if you eliminate a certain type of cell from mice, then they live quite a bit longer. Even if you do that elimination rather late; in other words when they're already in middle age." For those following the field, this was exciting news, but for de Grey, it was concrete proof that ageing can be combated. "That's the kind of thing that I've been promoting for a long time, and it's been coming but it's been pretty tricky to actually demonstrate directly. This was really completely unequivocal proof of concept," he says. "So of course it motivates lots of work to identify ways to do the same thing in human beings. These kinds of things are happening all the time now."

Funding for ageing research is forever in short supply. SENS is always asking for donations, and there is always more research to be done than there is money to fund it. However, this is starting to improve, both for SENS and for other institutions engaging in this field of research. In particular, the investment community has shown growing interest in ageing research. February's breakthrough findings were funded by private investors, and SENS, too, is spinning out some of its research into companies. The growing involvement of private investors is, according to de Grey, evidence of the changing perceptions of ageing research. "Not only is the science moving forward, but the appreciation of the science within the investor community is also moving forward. And that is absolutely critical to what we can expect to see in the future."

Reversing old age won't just be for rich people, says visionary biologist

Living longer "is the thing that's going to matter the most to people, Aubrey de Grey says, comparing it to the "It's the economy, stupid," tagline that Bill Clinton used on his road to the White House in 1992. "Ultimately, this is what people are going to vote for," he says. "If it's not available to everybody, then a party that has a manifest commitment to making it for everybody is going to get elected."

Then there are the economics of aging. "At the moment, when people get sick, it's incredibly expensive," de Gray says. "Probably 90% of the medical budget of the industrialized world goes to the diseases and disabilities of old age one way or another. That's trillions and trillions. If we can stop people from going that way by only spending billions, it's a big net win."

Additionally, if people can stay able bodied into their 80s, 90s, and beyond, then they can keep contributing their wealth to society, he says. Adding to collective wealth rather than drawing from it - which is why the "graying" of countries like Japan puts so much stress on an economy. "Therapies will pay for themselves in no time at all. and that means from a government's point of view, even the government of a really tax-averse country like the USA, it would be economically suicidal not to frontload the investment to ensure that everyone got these therapies as soon as possible." So living longer wouldn't just be a luxury good; it would be, to borrow from Bill Gates, a global public good.

In many ways the instinctive opinions that people hold on the economics of rejuvenation therapies are just as strange as their instinctive opinions on the desirability of rejuvenation and longer healthy lives. Many people say that they don't want to live a long time, and indeed don't want to live any longer than their parents. Similarly, most people will tell you - without really thinking about it - that longevity therapies would be enormously expensive and only available for the wealthy. This is actually far from the case.

Quite distinct from de Grey's points above, there is the fact that SENS rejuvenation therapies will be largely a matter of mass-produced infusions of small molecule drugs, enzymes, and gene therapies, the same treatment for everyone, given by a bored clinician in a brief visit once every few years. Some may be one-time treatments, such as autologous expression of mitochondrial DNA, leaving you set for life. The first senescent cell clearance treatments presently under clinical development consist of drug combinations and a gene therapy approach. Analogous treatments today, such as the biologics used to treat autoimmunity, or simple stem cell transplants, run to a few thousand per dose even in the dysfunctional US medical system. The economics of production, competition, and scale for medicine of this nature, in which all of the complexity is baked into the manufacturing process, are very different from those of enormously expensive treatments such as organ replacement and other challenging surgeries that require dedicated specialists and long periods of aftercare. Yet people continue to think that longevity therapies will be enormously expensive and reserved for the wealthy, and it seems hard to sway them from this opinion with mere logic.


Here I'll point out a recent and very readable open access review on the topic of mitochondrial contributions to the aging process. If you'd like a high level tour of present mainstream research community thinking on the numerous mechanisms that link or may link mitochondria to aging, this is a good place to start. Where it falls down, as is often the case, is in the process of moving from the data, that mitochondria contribute to aging, to what to do about the data, meaning strategies for the development of therapies to address mitochondrial dysfunction. When considering that goal, most present research groups immediately reach for pharmaceutical development with an eye to altering mitochondrial activities, such as by artificially recreating some of the calorie restriction response known to both reduce mitochondrial dysfunction and slow aging. The anticipated outcomes are not ambitious - a modest slowing in the progression of dysfunction at best - while the costs and uncertainties of pharmaceutical development to manipulate aspects of cellular metabolism remain as great as ever.

Mitochondria swarm in their hundreds inside each of our cells. They are the remnants of symbiotic bacteria from the earliest era of evolution, over time losing all but a fraction of their original genome. That remnant mitochondrial DNA (mtDNA) passes from mother to offspring, and there are a comparatively small number of varieties across the entire human population, each springing from a single ancestral mutation. Mitochondria multiply like bacteria, and are culled when damaged by quality control mechanisms inside the cell. They also merge, promiscuously swap protein assemblies and DNA, and can even transfer between cells, all of which makes understanding their behavior and the consequences of that behavior quite the challenge. Mitochondria play numerous crucial roles in the cell: they generate fuel for cellular processes in the form of adenosine triphosphate (ATP), and steer forms of programmed cell death such as apoptosis, for example.

In the SENS view of mitochondria in aging, it is the mitochondrial DNA that is critical. This DNA is both less stringently maintained than is our nuclear DNA and more vulnerable to damage. It sits right next to the highly energetic process of ATP production inside each mitochondrion, a process that produces reactive, potentially damaging molecules as a side-effect. Some rare forms of damage to mitochondrial DNA can deny necessary protein machinery to the mitochondrion, and as a result spawn dysfunctional mitochondria that are unfortunately also resilient to removal by quality control mechanisms. The damage multiples every time such a mitochondrion divides and replicates its broken DNA. These damaged mitochondria can quickly take over their cell, turning it into a source of damaging, reactive molecules that can spread throughout tissues and the bloodstream. The count of these cells grows with age: it is all a numbers game, a rare event that happens often enough to create a small class of cells that contribute significantly to age-related disease and dysfunction.

The complete fix for this particular contribution to the aging process, rather than just slowing it down, is to find some way to reliably and globally deliver the missing proteins that are encoded by broken mitochondrial genes. The possible approaches include: gene therapy to deliver new mitochondrial DNA or destroy the broken DNA; delivery of entire fresh mitochondria so that cells can adopt them; direct treatment with the necessary proteins, wrapped in delivery mechanisms that can get them to the mitochondria where they are needed; or the present SENS methodology of allotopic expression in which gene therapy is used to deliver suitably edited versions of mitochondrial genes into the cell nucleus, creating a permanent backup supply of the necessary protein machinery. These are all works in progress, but allotopic expression of single mitochondrial genes to treat inherited mitochondrial disease has, with the help of SENS Research Foundation funding some years ago, now reached the stage of serious biotech industry development. None of this is mentioned in the review paper below, and this is typical of much of the research community, sadly.

The Mitochondrial Basis of Aging

While, from an evolutionary viewpoint, the notion of antagonistic pleiotropy has been exclusively applied to our genetic inheritance, it actually provides a useful framework to understand the role of mitochondria in aging. Perhaps, no structure is so intimately and simultaneously connected to both the energy of youth and the decline of the old. The revelation of these complex and antagonistic functions of mitochondria has slowly transformed how we view this subcellular organelle. Mitochondria can no longer be viewed as simple bioenergetics factories but rather as platforms for intracellular signaling, regulators of innate immunity, and modulators of stem cell activity. In turn, each of these properties provides clues as to how mitochondria might regulate aging and age-related diseases.

It has been long appreciated that aging in model organisms is accompanied by a decline in mitochondrial function and that this decline might, in turn, contribute to the observed age-dependent decline in organ function. Similarly, a decline in mitochondrial function in humans has also been observed; again, this decrement may predispose humans to certain age-related diseases. It is also known that mitochondrial mutations increase in frequency with age in both animal models and in humans, although the levels and kind of mutations appear to differ between tissues and even within tissues. While some have speculated that the increased levels of mitochondrial mutations contribute to aging and age-related diseases, others have questioned whether these mutations ever reach a significant enough level to contribute to the aging process.

Mitochondria as Regulators of Stem Cell Function

While aging is accompanied by a general decline in mitochondrial function in all tissues, the effects of mitochondrial dysfunction might be particularly important within certain specialized cell types. Since a decline in adult stem cell function is thought to contribute to various aspects of aging, the role of mitochondrial dysfunction in stem cell biology has become a subject of increasing interest. One clear connection between mitochondria and stem cell function has come from the analysis of mtDNA mutator mice. Several reports have analyzed the stem cell function of these mice and found a range of defects. It should also be noted, that the level of mitochondrial mutation seen in these models is also dramatically higher than that seen during the normal aging process, which may account for why the observed stem cell defects do not faithfully recapitulate what is seen during normal aging.

Mitochondria and Cellular Senescence

There is a strong link between mitochondrial metabolism, reactive oxygen species (ROS) generation, and the senescent state. Almost four decades ago, it was noted that the lifespan of human cells in culture could be significantly extended by culturing the cells in a low-oxygen environment. Similar relationships have been observed between other regulators of senescence and ROS, including the p53 target and cell-cycle regulator p21, which also appears to regulate senescence in a redox-dependent fashion. All of these observations fit well with the long-standing notions of the free-radical theory of aging that postulated a causal role for ROS in the aging process. Nonetheless, there are a number of observations that suggest that the cellular effects of ROS, with regard to inducing senescence, do not unequivocally transfer to organismal aging.

The Mitochondrial Unfolded Protein Response and Longevity

The mitochondrial unfolded protein response (UPRmt) is a stress response pathway initially characterized in mammalian cells in which there was either a depletion of the mitochondrial genome or accumulation of misfolded proteins within the mitochondria. In either case, it was noted that this mitochondrial perturbation triggered a nuclear transcriptional response that included the increased expression of mitochondrial chaperone proteins. While initially described in mammalian cells, the biochemistry and genetics of this pathway have been predominantly studied in C. elegans. It is now clear that the UPRmt regulates a large set of genes that not only involve protein folding but also involve changes in ROS defenses, metabolism, regulation of iron sulfur cluster assembly, and, modulation of the innate immune response. In general terms, all of these changes allow for a restoration of mitochondrial function while, at the same time, re-wiring the cell to temporarily survive as best as possible without the benefit of full mitochondrial capacity.

Mitophagy in Aging

If misfolded proteins stemming from mtDNA mutations or proteotoxic stress accumulate to a level that exceeds the capacity of the UPRmt, autophagy of mitochondria (mitophagy), or piecemeal autophagy of mitochondrial subdomains, appears to mitigate mitochondrial impairment. Consistent with the suggestion that mitophagy protects animals from loss of mitochondrial function during aging, mitophagy rates decrease in the dentate gyrus with age and upon human huntingtin overexpression.

Mitochondria and Inflammation

One of the hallmarks of aging is the development of a low-grade, chronic, sterile inflammatory state often deemed "inflammaging". The development of this state, characterized in part by increased circulating inflammatory biomarkers such as interleukin (IL)-6 and C-reactive protein, is a known risk factor for increased morbidity and mortality in the elderly. Increasingly, there is a connection between mitochondrial function and the activation of this enhanced age-dependent immune response. Mechanistically, this connection can, perhaps, be traced back to the bacterial origins of the present-day mitochondria. As opposed to nuclear DNA, mtDNA (like bacterial DNA) is not methylated. The immune system has adapted to this subtle difference and has evolved strategies to recognize non-methylated DNA, primarily through members of the Toll-like receptors, including TLR9. Presumably, this response allows rapid activation of the immune system in the setting of bacterial infection. Besides releasing non-methylated DNA, damaged mitochondria, like bacteria, can release formyl peptides that can signal through the formyl peptide receptor-1 to trigger an immune response. Both mtDNA and mitochondrial formylated peptide can be viewed as mitochondrial-derived damage-associated molecular patterns (DAMPs) that are known to stimulate the innate immune system.


Taken together, these observations suggest that mitochondria can be intimately linked to a wide range of processes associated with aging, including senescence and inflammation, as well as the more generalized age-dependent decline in tissue and organ function. In many of the early studies, the association between mitochondria and the aging process was mostly correlative. Increasingly, however, causative connections are being established. This suggests that attempts to rejuvenate mitochondrial function or improve mitochondrial quality control might be an effective strategy to combat aging. Toward this goal, there are a number of ongoing efforts to develop small molecules to therapeutically augment mitochondrial biogenesis. Similarly, raising NAD+ levels in older mice appears to restore mitochondrial function. As such, there is considerable enthusiasm to develop methods to increase NAD+ levels, either through direct supplementation or by altering NAD+ metabolism. Pharmacologic activation of mitophagy is another approach that might be widely beneficial in patients with age-related neurodegenerative disorders or to combat aspects of normal aging. As such, the next decade appears to hold considerable promise for developing a wide range of effective mitochondria-targeted therapies. With such agents, clinical trials can ultimately test the very tenable hypothesis that reversing the decline in mitochondrial function will slow, or even reverse, the rate at which we age.


In the paper linked below, the authors report on an attempt to make senescent cells less damaging to surrounding tissues and overall health by modulating their behavior via inhibition of TNF-α, a signaling molecule involved in inflammation. Senescent cells accumulate with age and secrete a mix of molecules - the senescence-associated secretory phenotype (SASP) - that cause all sorts of harmful effects. The more senescent cells there are in any given part of the body, the worse the outcome: chronic inflammation, tissue dysfunction, and raised cancer risk are among the consequences. Accordingly, the presence of senescent cells is known to contribute to the development and pathology of most of the common age-related conditions. Removal of senescent cells has been shown to extend life in mice, but among the researchers who work in this field, there is in fact no great consensus that removal is the best approach. This approach is being taken nonetheless, and two startups, Oisin Biotechnologies and UNITY Biotechnology, are working on commercial development of their approaches to selective destruction of senescent cells. Still, there are those who would rather aim at using pharmacology to adjust the behavior of senescent cells to suppress the worst aspects of their behavior.

For my money, I want to see destruction rather than manipulation. It absolutely and definitely gets rid of whatever bad things senescent cells might be doing, including all the bad things that the research community is still the process of cataloging, or don't yet know about. The recent life span study in mice gives us a good assurance that the useful contributions that senescent cells may be making to our health, such as their roles in wound healing and reduction of cancer risk when they are few in number, are not going to be impacted significantly by periodic clearance. Manipulation of cell behavior, on the other hand, doesn't have an auspicious history of producing more than incremental gains. The way things tend to work is that researchers find a mechanism, often via gene engineering in mice, that produces some beneficial outcome. They then dig through the catalog of approved medicines, herbs, and other odds and ends in search of something that adjusts the same gene or protein level to some degree, while causing side-effects that are not unbearable. At the end of the day, a very diluted effect is the median outcome, achieved at great cost.

So given the option between (a) a straightforward effort that can rid of senescent cells and their effects near-entirely, and which already has methods under development, and (b) the standard lengthy and expensive drug development process that in the end may produce a modest reduction in the harmful output of senescent cells, and which currently has no good drug candidate in the works, the first of those choices sounds a lot better to me. Still, as I mentioned, a fair number of researchers are focused not on removal of senescent cells but rather on tinkering with adjusting the metabolism of senescent cells so as to reduce the impact of the senescence-associated secretory phenotype. Here is one example:

Anti-TNF-α treatment modulates SASP and SASP-related microRNAs in endothelial cells and in circulating angiogenic cells

The senescence status of stromal cells, including endothelial cells (ECs), plays a major role in inflammaging, the low-grade, chronic, and systemic inflammatory condition associated to aging. Cellular senescence is related to the acquisition of a discrete phenotype, the so called senescence-associated secretory phenotype (SASP), characterized by the activation of a pro-inflammatory transcriptional program. Accordingly, the pathways involved in SASP acquisition, as the NF-kB and the IL-1/NLRP3 inflammasome pathways are master modulators of the aging rate. Notably, removal of senescent cells in animal models, is able to prolong lifespan and healthspan. Evidence that the number of senescent dermal fibroblasts correlates with the presence of some age-related diseases has also been reported in humans.

Interventions directed at preventing the adverse effects associated with the SASP are being explored The most promising strategies involve delaying cellular senescence; SASP switch-off; and selective removal or killing of existing senescent cells. Even though SASP involves the release of hundreds of molecules, like interleukin (IL)-1, IL-6, IL-8, tumor growth factor (TGF)-β, and tumor necrosis factor (TNF)-α, the most common and best characterized. Some of these cytokines can induce or reinforce the senescent phenotype by acting in autocrine and paracrine manner, spreading senescence via a "bystander effect." However, TNF-α inhibition in relation to EC senescence and SASP acquisition has not been already extensively explored yet. TNF-α can promote senescence in endothelial progenitor cells and human umbilical vein endothelial cell (HUVEC) cultures, and it has well-known adverse effects on endothelial function in vivo. However the molecular basis for these effects has not been fully elucidated yet.

Here we tested whether TNF-α blockade can reduce the acquisition of the senescent phenotype and/or the SASP by HUVECs, an in vitro EC model. We documented that inhibition of TNF-α activity in ECs undergoing replicative senescence attenuated the SASP. Importantly, anti-TNF-α treatment also induced eNOS up-regulation, suggesting an enhanced endothelial function. Interestingly, these significant effects induced in HUVECs undergoing replicative senescence were not associated with significant decrease of classic senescence biomarkers, such as SA-β-Gal, p16/Ink4a, and PAI1.

Some studies have described the possibility of dissociating experimentally the SASP from senescence. Although a number of reports have shown that SASP modulation influences the rate of senescence, differences have been observed depending on the cytokines involved. In our experimental model, i.e. HUVECs undergoing replicative senescence, the number of senescent cells was not significantly affected by continuous anti-TNF-α treatment, suggesting that TNF-α is not closely associated with the arrest of replicative growth. Although it has been demonstrated that IL-1 or TGF-β blockade can attenuate SASP spread in different senescence models, data on anti-TNF-a treatment were scarce and inconclusive. The present findings now indicate that anti-TNF-α treatment can restrain the SASP without significantly affecting senescence signal transmission, either autocrine or paracrine.

In conclusion, anti-inflammatory treatments capable of restraining the SASP could contribute to delay age-related disease onset and progression, especially in patients with an established chronic inflammatory background. Clearly, TNF-α inhibition has too many side effects to be administered as a clinical anti-aging treatment in old patients. However, the present findings are in line with earlier reports that it is possible to dissociate the SASP from senescence, and encourage the search for substances, synthetic or natural, that not only suppress but also restrain the SASP. Our data adds a piece to the complex puzzle of inflammaging, furthering our knowledge of the mechanisms controlling the SASP in ECs and the associated chronic inflammation that can promote the development and progression of the major age-related diseases.


Some very few humans live for decades longer than the average, and the available evidence suggests that at very late age - and ever increasing frailty - genetic variation becomes an increasingly important determinant of longevity. To be clear, almost everyone with a superior genome dies before reaching a century of age: the odds of making it that far are tiny regardless of your genes. But all it takes is a small increase in those tiny odds to ensure that the present population of very old people is weighted in favor of those who are slightly more resilient. So don't imagine that this is something worth recapturing in a therapy. The study of genetics and natural variations in human longevity will, I suspect, be a transitory curio of our short era. We stand in a thin slice of history in which medical technology is advanced enough to catalog genetics and cellular biochemistry, but still too primitive to bring aging under medical control. There isn't much of a gap between those two thresholds of progress; the second follows quite quickly after the first. After rejuvenation therapies are developed, well within the lifetimes of most of those reading this today, after the creation of a comprehensive toolkit to repair all of the forms of cell and tissue damage that cause aging, few people will ever get to the point of being so damaged that their genes are relevant to how long they can survive in that reduced state. There will be little interest in the study of the condition of being aged. How many researchers study how genes affect the chance of surviving smallpox without modern treatments? Not many.

For today, however, the genetics of longevity is one of the more energetic parts of aging research, a field usually the neglected, poorly-funded stepchild of the medical research community. Genetics is a hot topic, and progress in biotechnology is causing both a dramatic fall in cost and dramatic increase in capabilities for the tools used by researchers. Great advances in gathering and understanding genetic data are made with each passing year. When you have a hammer, everything looks like a nail. Hence the existence of initiatives like Human Longevity, Inc., a well-funded young company mixing genetic data with personalized medicine and promising enhanced life spans on the horizon. I don't think they can deliver on that promise. I don't see that chasing human longevity-associated genetic variants is a path to anything other than producing larger databases with better maps of cellular biochemistry. That is an admirable course of action from a pure science perspective, but it won't lead to therapies capable of meaningfully moving the needle on human longevity. Useful treatments for aging, capable of adding decades or more of healthy life, are not going to emerge from understanding the networks of possibly hundreds of genes that make an individual slightly more rather than slightly less likely to live to 100. They are only going to arise from directly addressing the known forms of cell and tissue damage that cause aging.

As this open access paper points out, the genetic networks influencing survival at late ages are large and very complex. Studies attempting to map these networks tend to produce data that cannot be replicated in different populations, indicating very large numbers of relevant genes, each with a tiny individual effect, and all very dependent on one another and on environmental circumstances.

Genetics, lifestyle and longevity: Lessons from centenarians

While the average life expectancy in the US is approaching 80 years, the mean life span of centenarians (and super-centenarians) is about 112. As a group, they represent a distinct region of the demographic distribution among the contemporary human populations. In other words, assuming that the average human generation time is about 25, centenarians are endowed with an extra human generation time. Besides, they are known to have a better health profile relative to the people with normal life span. These distinguishing features of centenarians have prompted an interest among demographers, health scientists and the general public alike, to explore the possibilities of extending the life span of cosmopolitan population to approach that of centenarians. Therefore, we consider their distinct features from an evolutionary, genetic, developmental and environmental perspective, as these factors have been suggested to influence quantitative traits universally. First, centenarians occur at a frequency of about 1.73 and 3.43 per 10000 individuals in the U.S. and Japan respectively; hence they are rare. Second, among genetic factors, certain genotypes/alleles that are known to influence longevity are enriched among centenarians (e.g., Apo C3-CC; FOXO3a-T; CETP-VV; AdipoQ-del/del; TSHr-G and IGFr). Third, others have suggested that longevity may be a function of genomic integrity. Although evidence on this important idea is relatively sparse on centenarians, research has reported low levels of chromosomal aberrations (an index of superior genomic integrity), relative to cosmopolitan populations. It is suggested that the relatively low level of chromosomal aberrations in the "oldest old" people may be both a consequence of their genomic stability and a contributing factor to their attainment of advanced age.

At the genomic level, anywhere between 300-700 genes (or perhaps more) may be influencing longevity. Although this appears to be a large number, in a recent study on human height, which is arguably a less complex trait than longevity, it was reported that 697 variants among 423 genomic regions may be influencing the trait, and speculated that perhaps thousands may be involved. A similar argument could be advanced for longevity, because longevity as a life history and as an indeterminate trait, is influenced by traits that contribute to both viability and reproductive fitness from zygotic stage through adult stages, till death. Note that a number of genes that influence human height also influence longevity (e.g., IGF1 and mTOR) and other life-history traits, such as body weight and sexual maturity, due to pleiotropy. Life history traits often display genetic correlation due to the underlying pleiotropic effects of genes. Further, life history traits maintain allometric relationships, and consequently show trade-offs in their functional aspects. Accordingly, genes that influence longevity could exert both differential and contextual influence on specific traits as well as correlated antecedent traits during the aging process, as shown by divergent patterns of methylation among age groups. These recent discoveries on the developmental regulation of aging, among contrasting age groups, using comparative gene expression, largely compliment previous reports on genotype-phenotype relationships.

The biological basis of exceptional health and longevity among centenarians has remained unclear. The general features of exceptional longevity, however, appears to run in families, and as a group they have a natural tendency to maintain good health much of their lives. Although centenarians are found to occur at higher frequencies in certain geographical locations, their life-style may not be significantly different from individual members of cosmopolitan populations who chose to lead a healthy life-style. It is likely that centenarians differ from each other just as individuals with normal life span do. Yet, individuals with exceptional longevity may interact with environmental and lifestyle factors differently than others. This unique feature may be interpreted as a form of genotype × environment interaction. As a parsimonious explanation, from a genomic perspective, exceptional longevity of centenarians may be attributed to their superior genomic integrity, specific polymorphisms among genes such as ApoC3-CC, FOXO3aT, and CETPVV, and associated molecular genetic and physiological homeostatic mechanisms. It is likely that centenarians arise and are maintained by negative frequency-dependent selection, as this mode of selection has been shown to have slightly superior physiological mechanisms relative to more common genotypes in general populations. There may be other mechanisms, however, and needs further investigation.


A legitimate, actual human rejuvenation therapy is one that repairs one of the forms of cell and tissue damage that are collectively the root cause of aging. By root cause I mean that this damage occurs as a result of the normal operation of cellular metabolism, and is not itself caused by another form of damage. The present list includes a few classes of persistent metabolic waste, such as misfolded proteins and sugary cross-links, mitochondrial DNA damage, senescent cells, cancerous nuclear DNA mutations, and loss of necessary cell populations, such as active stem cells and long-lived cells in the central nervous system. While not directly caused by one another, these various forms of root cause damage do interact with one another. One type of damage can speed up the progression of another independent form of damage by harming quality control or repair mechanisms, for example.

Do any real, legitimate rejuvenation therapies exist yet? Why yes, as it happens. In 2015, Pentraxin Therapeutics and GlaxoSmithKline completed a small trial of a therapy capable of partially clearing transthyretin amyloid in human patients. Amyloids are misfolded protein, a type of persistent metabolic waste that accumulates in all of us with age, and which in this case is implicated in the development of cardiovascular disease, among other conditions. The presence of amyloid in older tissues is a form of damage, and clearing it is a form of repair, and thus a narrow and specific form of rejuvenation. A little way behind Pentraxin is Oisin Biotechnology, a new startup with a working gene therapy approach that selectively destroys senescent cells. That has been tested in rats rather than people, but the only reasons it couldn't be used in humans today, right now, are the heavy hand of regulation on the one hand, and a desire for another year or so of work to underline the proof of function on the part of the founders on the other. Beyond these two, there are a few other cases in which thinner slices of the necessary technologies for rejuvenation are under development. For example Gensight is putting a lot of effort into human trials for allotopic expression of a single mitochondrial gene to treat inherited conditions in which that gene is mutated. There are thirteen genes that need this treatment if the technology is to be used for rejuvenation, to completely block the contribution of mitochondrial DNA damage to aging, so in a sense Gensight is building a 1/13th slice of a rejuvenation therapy.

You can't undertake any of these treatments today, however, or at least not unless you are wealthy, connected, and persuasive, in which case you buy early access to the treatment by funding a company to develop it and becoming an insider. Even that is only an option if the people doing the work are willing to go along with it, which isn't always going to be the case. A lot of developers want to walk the regulatory path with clear compliance, which means that it could take a decade or more from start to finish before anyone other than a qualified trial participant undergoes any version of the treatment. That is clearly the case for the Pentraxin work on transthyretin amyloid, which has been locked up in the Big Pharma development and regulatory process for seven years already, and may well be years yet in getting to the clinic. When it does, the odds are it will be restricted for use for specific age-related conditions in their later stages, and it will take further time to break it out into more general availability. This is how things tend to progress in the formal, regulated development process. It takes a very long time for even spectacularly successful technologies to become available to the general public.

This is not what we'd like to see happen for rejuvenation therapies. Adding five or ten entirely unnecessary years between the first functional, proven therapy and availability of that therapy in clinics seems crazy given the immense cost of aging and age-related disease. Ideally the initial developer of a rejuvenation therapy could license the technology to groups willing to spend the excessive time and money needed to go through the regulatory hurdles put in place - largely for no good reason - by the FDA and their equivalents. Then that developer can focus on putting the therapy into clinics immediately through other channels. This is not a novel idea. It is exactly what happened during the early stages of clinical availability of stem cell therapies outside the US and Europe, in the years immediately following the turn of the century. That produced a great deal more data and beneficial results for patients that would have been the case had everyone followed the demands of regulators. It took the FDA a decade to approve any sort of stem cell therapy in the US, and that only happened because those therapies were widely available in many other countries, making regulators in the US look backward and obstructive. That is really the only way to improve regulation, to work around it, make it irrelevant, and make the actions of the bureaucrats involved appear exactly as foolish and malign as they are.

The first set of narrow rejuvenation therapies capable of repairing a slice of the damage that causes aging either work now or are only a year or two away away from working implementations. What are the paths to getting them into clinics and accessible via medical tourism shortly thereafter rather than locked away in the regulatory process for a decade? Two roads spring to mind. The first is to follow in exactly the same footsteps as the stem cell research and development community: every clinic capable of handling stem cell therapies is only a small step away from being able to deliver infusions of enzymes or even gene therapies. Most of the existing institutions of delivery, manufacturing, certification, and training that have come into being over the past decade could be utilized to deliver rejuvenation treatments alongside stem cell therapies. It isn't a big leap, and there are likely many solid and reputable allies to be made along the way. Stem cell therapies are a big business in many parts of the world now, such as India, China, and other Asia-Pacific countries, and the provision of such therapies is a maturing industry with players at every size, from hospitals to individual practices to associations and advocacy groups.

The second option is to engage with the big networks of the "anti-aging" industry, which currently sells exactly nothing (other than perhaps exercise and advice on calorie restriction) worthy of the name. This large and very vocal industry is the result of enthusiasm for intervention in the aging process that started in the 1970s, well in advance of any ability for medical science to produce meaningful results. It is a great example of the way in which it is possible to succeed in business while failing to achieve any of the original goals that drove the launch of that business. Having produced a pipeline and a network, and finding thereafter that there was no such thing as an "anti-aging" treatment at that time, this space became filled with a mix of nonsense, fraud, and useless frippery, pills, potions, and lies. The nonsense won't magically vanish overnight with the advent of real rejuvenation therapies, but if you go dig through the materials available via organizations such as the Life Extension Foundation or the American Academy of Anti-Aging Medicine, you'll see that there are thousands of physicians involved in this business. Of these, many are associated with clinics capable of delivering mass-produced infusions and gene therapies, and have experience with established mechanisms of provision, training, and certification. More to the point this is an industry with a fair degree of centralization in its points of contact, the conferences and industry groups like A4M are good ways for a developer of actual, real rejuvenation treatments to reach this market.

The question here is whether the intangible costs of the second option are worth the benefits. Is the "anti-aging" marketplace so terrible that it is capable of sinking a legitimate rejuvenation therapy and company by mere association? If plastic surgeons or "anti-aging" clinics start to sell senescent cell clearance injections in addition to their normal wares, is that the good chasing out the bad, or the good being corrupted and confused in the public eye so that support for progress in the medical control over aging becomes even harder to obtain? It is hard to say one way or another - it is one of those things that probably depends on the details.


Monday, March 14, 2016

The folk leading the Major Mouse Testing Program are here interviewed on their work. This volunteer initiative aims to crowdfund mouse life span studies of useful approaches to lengthening healthy life spans in mammals, including SENS rejuvenation research methodologies as they become possible to carry out, such as senescent cell clearance. There are a fair number of such studies that could be carried out, but in most cases the few champions in the research community have struggled to raise funding and engage broader interest. This was the state of affairs for senescent cell clearance up until very recently, but no-one can really argue with the data for life extension in mice via this method that now exists - so it is certainly the case that very promising approaches for treating aging languish for lack of funding, but could be spurred forward by better data in mice.

The gap in the market we're aiming to fill is the bridge between basic research and taking it to clinical trials. People like the SENS Research Foundation are spinning a lot of plates doing the high risk, nitty gritty research that isn't profitable, but crowdfunding can get that done. We want to create a solid gold standard testing platform without the restrictions of government, where any team can come to us for parallel testing and halve development time. The problem with animal testing is there's this disconnect; it's not sexy science basically. A common response is let me know when it's available in humans, but it's not going to be! No animal data means no human testing, regulatory organizations like the FDA, NHS, and EMA all insist on a battery of animal testing before human trials. Period. It's not sexy, it's not available in humans next week, but if MMTP or other projects don't get things done on mice for example, it's never going to get done.

It's not just about the science, too many people claim to support longevity but don't actually do anything to contribute or get things moving. Right now we're pushing to promote ideas among decision makers at a wide range of levels - at the international level like the last World Health Organization Conference in Geneva and at the local level trying to stimulate the same process in multiple countries. There is a big problem with funding today, but if there's even the smallest chance to stimulate movement and make a bigger research impact, we've got to do it.

We can't rely on a traditional model of funding like the FDA, EMA and other government organizations. They may fund some ventures, but it's never going to be the avalanche of support we need to get things done in a timely manner. The pace of progress is glacial in that model. We can't afford to just preach to the choir unfortunately, we need to make bigger waves. Advanced glycation end-products (AGE) breakers for example is one treatment we'd like to explore, and AGEs are closely implicated with diabetes and atherosclerosis, which means we could potentially draw on mainstream and charity support if the data is there to support it. We've got to cast a wide net ultimately or we're not going to go anywhere near fast enough; it's that simple.

We're back to the problem of the mindset here, too many people have this idea that aging isn't amenable to intervention and yet they're quite happy to fund disease research for age-related diseases like Alzheimer's. The money is out there, but we need to be more tactical in how we pursue it. The 1st phase of testing using senolytics to clear senescent cells is quite a difficult concept to sell, but the more we learn and the more robust results we get, the more we can capture hearts and minds. No-one is taking any wages either, which it's why it's so cheap and we can achieve a lot more.

Monday, March 14, 2016

This popular press article takes a look at some of the people involved in the early stage scientific foundations that will be needed to eventually run a human mind in software. Many of these advocates see mind uploading as a viable end goal for the defeat of aging - to transition away from biology entirely towards emulation of the mind in software. This has always seemed to me to be a potentially dangerous distraction from the business of ensuring personal survival. In most cases the advocates of uploading consider that making a copy of the data of the self is an acceptable form of continuation of identity, but in fact that isn't personal survival at all. The self isn't just data absent context, it is the combination of data and the particular collection of matter than encodes it: thus you are not your copy, these are two individuals made up of two separate collections of matter.

Yes, it is technically possible to transition away from biology in ways that might preserve the self. Consider a slow swapping out of neurons for nanomachines, one by one, for example, a personal Ship of Theseus in which transitions run little differently from the present processes of neurogenesis in the adult brain. That isn't the direction of interest for most of the community presently putting in effort on the very early groundwork needed to abandon our biology, however. Their aim is often simply scanning of the brain, a straight copy.

While many tech moguls dream of changing the way we live with new smart devices or social media apps, one Russian internet millionaire is trying to change nothing less than our destiny, by making it possible to upload a human brain to a computer. "Within the next 30 years," promises Dmitry Itskov, "I am going to make sure that we can all live forever." Itskov is putting a slice of his fortune in to a bold plan he has devised to bypass ageing. He wants to use cutting-edge science to unlock the secrets of the human brain and then upload an individual's mind to a computer, freeing them from the biological constraints of the body. The scientific director of Itskov's 2045 Initiative, Dr Randal Koene - a neuroscientist who worked as a research professor at Boston University's Center for Memory and Brain - laughs off any suggestion Itskov might have lost touch with reality. "All of the evidence seems to say in theory it's possible - it's extremely difficult, but it's possible. The challenge is precisely how to go from a physical substrate of cells that are connected inside this organ, to our mental world, our thoughts, our memories, our feelings."

To try to unlock its workings, many neuroscientists approach the brain as if it were a computer. In this analogy the brain turns inputs, sensory data, into outputs, our behaviour, through computations. This is where the theoretical argument for mind uploading starts. If this process could be mapped, the brain could perhaps be copied in a computer, along with the individual mind it gives rise to. That's the view of Dr Ken Hayworth, a neuroscientist who maps slivers of mouse brain at the Janelia Research Campus in Virginia by day, and by night grapples with the problem of how to upload his mind. Ken believes mapping the connectome - the complex connections of all the neurons in a brain - holds the key, because he believes it encodes all the information that makes us who we are, though this is not proven. "In the same sense that my computer is really just the ones and zeros on my hard drive, and I don't care what happens as long as those ones and zeros make it to the next computer it should be the same thing with me. I don't care if my connectome is implemented in this physical body or a computer simulation controlling a robotic body."

Ken is a realist. "We are pitifully far away from mapping a human connectome." Here Itskov might get some unexpected help, according to Prof Rafael Yuste of Columbia University - who helped bring about the world's biggest neuroscience research project, the Brain Initiative. As part of this 6 billion American programme aimed at solving the mysteries of brain disorders like Alzheimer's, he is hoping to map the continual interaction of neurons - the patterns of firing - in the brain over time. Within 15 years Yuste hopes to map - and interpret - the activity of all the neurons in a mouse cortex. But the ultimate aim is to read the activity of the human brain. "If the brain were a digital computer, if you wanted to upload the mind you need to be able to decipher it or download it first. So I think the Brain Initiative is a step that is necessary for this uploading to happen."

Tuesday, March 15, 2016

Age-related macular degeneration is a condition that causes progressive blindness. The less common wet variety of macular degeneration is characterized by an excessive and damaging growth of blood vessels in the retina. Researchers here map some of the signals and changes that take place in response to dysfunctional energy metabolism in retinal cells, seeing this as a cause of the condition:

Both wet age-related macular degeneration (AMD) and macular telangiectasia are caused by abnormal growth of misshapen, leaky blood vessels in the eye's retina. It's widely believed this growth is triggered by oxygen deprivation. However, new findings suggest another cause: dysfunctional energy metabolism in the eye that starves the retina's light receptors of fuel. Photoreceptors consume a surprising amount of fuel. They have the highest concentration of mitochondria and use more energy than any other cell in the body. They have to be 'on call' all the time to signal light perception and have to recycle their components constantly. Because of this, photoreceptors have evolved a special system to ensure they get enough fuel. While these cells were assumed to be powered by glucose, the study showed that photoreceptors also need lipids, or fats. They have special receptors to take up fatty acids, as well as a special lipid sensor, FFAR1, that curtails glucose uptake when fatty acids are available.

When blood lipids are elevated, the lipid sensor FFAR1 shuts off glucose uptake inappropriately. The energy-starved photoreceptors then call for new blood vessels to bring them nutrients by secreting large amounts of vascular endothelial growth factor (VEGF). This signaling protein is known to encourage abnormal blood-vessel formation in macular disease. VEGF blockers exist and already being used in AMD, but they have systemic side effects, preventing healthy, necessary growth of blood vessels. "If you go upstream of VEGF and solve the energy problem early, it could be more effective and safer." It may be possible to do that by blocking the lipid sensor, FFAR. In experiments where researchers did this, cells were able to keep taking in glucose and the mice had far fewer diseased vessels. The transporter that brings glucose into cells is another potential target, but is harder to reach with drugs, whereas FFAR inhibitors are already in clinical trials for diabetes.

The researchers believe that fuel starvation contributes to age-related macular disease due not only through lack of fuel but also decreased energy efficiency in mitochondria as people age. Abnormal lipid metabolism and mitochondrial dysfunction are both associated with aging and are important risk factors for AMD. The next steps will be to see if people have lipid sensors similar to those in mice. If so, existing inhibitors could be tried in clinical trials.

Tuesday, March 15, 2016

It is presently technically feasible to build small medical implants made of a mix of electronics, processors, drug manufactories, and tissues, which can be self-regulating or connected via wireless to external computing systems. The heavy hand of regulation in the medical industry ensures that such development in the field is far behind where it might be, particularly in matters of network security for medical technologies, but progress in the labs isn't as constrained - there is still some room there to build on the basis of what is possible rather than what regulators permit. Even in recent years most bioartificial implants under development have been much more device than tissue, such as those intended to replicate some of the functions of the pancreas, for example, but in this case researchers aim at building patches for damaged and aged hearts that are mostly cells with a thin layering of artificial components:

The bionic heart patch combines organic and engineered parts. In fact, its capabilities surpass those of human tissue alone. The patch contracts and expands like human heart tissue but regulates itself like a machine. "Until now, we could only engineer organic cardiac tissue, with mixed results. Now we have produced viable bionic tissue, which ensures that the heart tissue will function properly. We first ensured that the cells would contract in the patch, which explains the need for organic material. But, just as importantly, we needed to verify what was happening in the patch and regulate its function. We also wanted to be able to release drugs from the patch directly onto the heart to improve its integration with the host body."

For the new bionic patch, researchers engineered thick bionic tissue suitable for transplantation. The engineered tissue features electronics that sense tissue function and accordingly provide electrical stimulation. In addition, electroactive polymers are integrated with the electronics. Upon activation, these polymers are able to release medication, such as growth factors or small molecules on demand. "Imagine that a patient is just sitting at home, not feeling well. His physician will be able to log onto his computer and this patient's file - in real time. He can view data sent remotely from sensors embedded in the engineered tissue and assess exactly how his patient is doing. He can intervene to properly pace the heart and activate drugs to regenerate tissue from afar. The longer-term goal is for the cardiac patch to be able to regulate its own welfare. In other words, if it senses inflammation, it will release an anti-inflammatory drug. If it senses a lack of oxygen, it will release molecules that recruit blood-vessel-forming cells to the heart."

Wednesday, March 16, 2016

Researchers here report on one of many attempts to slow aging via manipulation of antioxidant levels in cells, finding that the results are gender-specific. Over the past decade there have been mixed results from animal studies that use gene therapy and other methods to increase antioxidant levels in various parts of the cell. The idea is to reduce oxidative damage associated with aging, but it is not at all obvious that this is the mechanism by which aging is slowed in those approaches that do modestly extend life. The reactive oxidant molecules that cause damage are also signals, so changing the levels of these signals can have all sorts of effects on cellular metabolism, both positive and negative, and not all of which are fully understood at the present time. For example the general introduction of antioxidants throughout cells removes the benefits of exercise, as it blocks the mild increases in oxidative damage that the body reacts to in order to create those benefits. Targeting antioxidants to mitochondria only has produced modestly extended life spans with greater reliability, however.

The gradual accumulation of cell damage plays a very important role in the origin of ageing. There are many sources of cellular damage, however, which ones are really responsible for ageing and which ones are inconsequential for ageing is a question that still lacks an answer. The Oxidative Hypothesis of Ageing - also known as the Free Radicals Hypothesis - was put forward in 1956. Since then, the large majority of attempts to prove that oxidative damage is relevant for ageing have failed, including multiple clinical trials in humans with antioxidant compounds. For this reason, although the accumulation of oxidative damage with ageing is undisputed, most scientists believe that it is a minor, almost irrelevant, cause of ageing.

A group of scientists have tried to increase the global antioxidant capacity of the cells, rather than just one or a few antioxidant enzymes. To achieve this global improvement in the total antioxidant capacity, researches have focused on increasing the levels of NADPH, a relatively simple molecule that is of key importance in antioxidant reactions and that, however, had not been studied to date in relation to ageing. The researchers used a genetic approach to increase NADPH levels. In particular, they generated transgenic mice with an increased expression throughout their bodies of one of the most important enzymes for the production of NADPH, namely, glucose-6-phosphate dehydrogenase (or G6PD). "As anticipated, the cells in these transgenic animals are more resistant to highly toxic artificial oxidative treatments, thus proving that an increase in G6PD really improves antioxidant defences."

Furthermore, when researchers analysed long-lived transgenic animals, they noted that their levels of oxidative damage were lower than in non-transgenic animals of the same age. They also studied the propensity of these animals to develop cancer and found no difference, suggesting that enhancing G6PD activity does not have an important effect on the development of cancer. The greatest surprise for the team was when they measured the ageing process in the transgenic mice: the animals with a high G6PD expression and, therefore, high levels of NADPH, delayed their ageing, metabolised sugar better and presented better movement coordination as they aged. In addition, transgenic females lived 14% longer than non-transgenic mice, while no significant effect on the longevity of males was observed.

Wednesday, March 16, 2016

In recent years, researchers have used decellularization to strip cells from rat hearts, leaving behind the intact and intricate extracellular matrix structure, and then rebuilt a functional heart by seeding it with new cells. This approach has the potential to create patient-matched donor organs with minimal issues of immune rejection when transplanted, but there is still work to be done in order to reliably carry out the process in human hearts:

Researchers have taken some initial steps toward the creation of bioengineered human hearts using donor hearts stripped of components that would generate an immune response and cardiac muscle cells generated from induced pluripotent stem cells (iPSCs), which could come from a potential recipient. Using a scaled-up version of the process originally developed in rat hearts, the team decellularized 73 hearts from both brain-dead donors and from those who had undergone cardiac death. Detailed characterization of the remaining cardiac scaffolds confirmed a high retention of matrix proteins and structure free of cardiac cells, the preservation of coronary vascular and microvascular structures, as well as freedom from human leukocyte antigens that could induce rejection. There was little difference between the reactions of organs from the two donor groups to the complex decellularization process.

Instead of using genetic manipulation to generate iPSCs from adult cells, the team used a newer method to reprogram skin cells with messenger RNA factors, which should be both more efficient and less likely to run into regulatory hurdles. They then induced the pluripotent cells to differentiate into cardiac muscle cells or cardiomyocytes, documenting patterns of gene expression that reflected developmental milestones and generating cells in sufficient quantity for possible clinical application. Cardiomyocytes were then reseeded into three-dimensional matrix tissue, first into thin matrix slices and then into 15 mm fibers, which developed into spontaneously contracting tissue after several days in culture.

The last step reflected the first regeneration of human heart muscle from pluripotent stem cells within a cell-free, human whole-heart matrix. The team delivered about 500 million iPSC-derived cardiomyocytes into the left ventricular wall of decellularized hearts. The organs were mounted for 14 days in an automated bioreactor system that both perfused the organ with nutrient solution and applied environmental stressors such as ventricular pressure to reproduce conditions within a living heart. Analysis of the regenerated tissue found dense regions of iPSC-derived cells that had the appearance of immature cardiac muscle tissue and demonstrated functional contraction in response to electrical stimulation. "Regenerating a whole heart is most certainly a long-term goal that is several years away, so we are currently working on engineering a functional myocardial patch that could replace cardiac tissue damaged due a heart attack or heart failure. Among the next steps that we are pursuing are improving methods to generate even more cardiac cells - recellularizing a whole heart would take tens of billions - optimizing bioreactor-based culture techniques to improve the maturation and function of engineered cardiac tissue, and electronically integrating regenerated tissue to function within the recipient's heart."

Thursday, March 17, 2016

Longevity associated genes are not in fact robustly longevity-associated, as this study demonstrates, the researchers failing to find an association for even the very few gene variants thought to be fairly reliable in other data. The overwhelming majority of associations found between gene variants and human longevity have very small effects and cannot be replicated in different study populations, even in the same region of the world. This means that the impact of any individual gene variant on human longevity is tiny at best and non-existent at worst, and in either case that small effect is very dependent on other factors, either genetic or environmental. This suggests to me that comparative genetics, such as the study of centenarian biochemistry and cellular metabolism, is not a field with the potential to move the needle on human longevity; translating small and dubious effects into therapies capable of reproducing those effects just doesn't make sense when there are other, much better approaches to the treatment of aging.

In this study we explored the association between aging-related phenotypes previously reported to predict survival in old age and variation in 77 genes from the DNA repair pathway, 32 genes from the growth hormone 1 / insulin-like growth factor 1 / insulin (GH/IGF-1/INS) signalling pathway and 16 additional genes repeatedly considered as candidates for human longevity: APOE, APOA4, APOC3, ACE, CETP, HFE, IL6, IL6R, MTHFR, TGFB1, SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14.

Altogether, 1,049 single nucleotide polymorphisms (SNPs) were genotyped in 1,088 oldest-old (age 92-93 years) Danes and analysed with phenotype data on physical functioning (hand grip strength), cognitive functioning (mini mental state examination and a cognitive composite score), activity of daily living and self-rated health.

Five SNPs showed association to one of the phenotypes; however, none of these SNPs were associated with a change in the relevant phenotype over time (7 years of follow-up) and none of the SNPs could be confirmed in a replication sample of 1,281 oldest-old Danes (age 94-100). Hence, our study does not support association between common variation in the investigated longevity candidate genes and aging-related phenotypes consistently shown to predict survival. It is possible that larger sample sizes are needed to robustly reveal associations with small effect sizes.

Thursday, March 17, 2016

It isn't hard to kill cells; "bleach works just fine," as I was told by a researcher some years ago. The challenge lies in killing only a specific set of cells in a living organism, and without greatly harming the organism in the process. Obviously something more discriminating than bleach is called for. The mainstay of the last generation of cancer therapies, chemotherapy, is a fine balance between harming cancer cells as much as possible while harming the patient as little as possible. It isn't a pleasant experience, and it does have significant and lasting negative impact. The best that can be said of it is that it is much better than the alternative. The promise of new technologies allowing delivery of therapeutics to individual cells based on their specific differences in surface or internal chemistry is that existing chemotherapy drugs can be used with minimal doses and near-absent side effects, and yet still be more efficient when it comes to removing cancerous cells. This is one example of many targeted delivery mechanisms under development or in trials:

At the heart of the new therapy is a chemotherapeutic agent called doxorubicin (dox). The drug has been a mainstay of cancer treatment for years, as it jams up DNA in the cell nucleus and prevents tumor cells from dividing. But when it's injected into the bloodstream, the drug can also kill heart muscle cells and cause heart failure. Delivering dox only to tumor cells is therefore highly desirable, but it has been a major challenge. Thus researchers have spent years developing porous silicon particles as drug carriers. The particles' micrometer-scale size and disk-like shape allows them travel unimpeded through normal blood vessels. But when they hit blood vessels around tumors, which are typically malformed and leaky, the particles fall out of the circulation and pool near the tumor. That was step one in delivering chemotherapeutic drugs to their target. But just filling such particles with dox doesn't do much good. Even if a small amount of the drug finds its way inside tumor cells, those cells often have membrane proteins that act as tiny pumps to push the drug back outside the cell before it can do any damage.

To get large amounts of dox inside the metastatic tumor cells and then past the protein pumps, researchers linked numerous dox molecules to stringlike molecules called polymers. They then infused the dox-carrying polymers into their silicon microparticles and injected them into mice that had been implanted with human metastatic liver and lung tumors. The silicon particles congregated in and around tumor sites, and once there the particles slowly degraded over 2 to 4 weeks. As they did so, the silicon particles released the dox-carrying polymer strands. In the watery environment around tumor cells, the strands coiled up into tiny balls, each just 20-80 nanometers across. That size is ideal, because it's the same size as tiny vesicles that are commonly exchanged between neighboring cells as part of their normal chemical communication. In this case, the dox-polymer balls were readily taken up by tumor cells. Once there, a large fraction was carried internally away from the dox-exporting pumps at cell membrane and toward the nucleus.

Not only is the region around the nucleus devoid of dox-removing pumps, but it typically has a more acidic environment than near the cell membrane. The researchers designed the chemical links between dox molecules and the polymer to dissolve under acidic conditions. This releases the dox at the site where its cell killing potency is highest. Up to 50% of cancer-bearing mice given the treatment showed no signs of metastatic tumors 8 months later. The results are promising enough that the researchers are planning to launch clinical trials in cancer patients within a year. The new work holds out hope for improving the effectiveness of other chemotherapy drugs as well. "There's no reason to believe you couldn't make a version of these particles with any chemotherapeutic agent."

Friday, March 18, 2016

Researchers have demonstrated a successful and fairly straightforward stem cell therapy for osteoporosis in mice, though it remains a question mark as to exactly how it works under the hood. Osteoporosis is the name given to the age-related loss of bone mass and strength, with the primary proximate cause being a growing imbalance between the activities of osteoblasts that deposit bone and osteoclasts that absorb it. There are other factors involved, such as persistent cross-linking that makes the molecular structure of bone more fragile, but so far the best results in the laboratory have arisen from increasing osteoblast activity, reducing osteoclast activity, or both in conjunction.

With age-related osteoporosis, the inner structure of the bone diminishes, leaving the bone thinner, less dense, and losing its function. But how can an injection of stem cells reverse the ravages of age in the bones? Researchers had in previous research demonstrated a causal effect between mice that developed age-related osteoporosis and low or defective mesenchymal stem cells (MSCs) in these animals. "We reasoned that if defective MSCs are responsible for osteoporosis, transplantation of healthy MSCs should be able to prevent or treat osteoporosis."

To test that theory, the researchers injected osteoporotic mice with MSCs from healthy mice. Stem cells are "progenitor" cells, capable of dividing and changing into all the different cell types in the body. Able to become bone cells, MSCs have a second unique feature, ideal for the development of human therapies: these stem cells can be transplanted from one person to another without the need for matching (needed for blood transfusions, for instance) and without being rejected. After six months post-injection, a quarter of the life span of these animals, the osteoporotic bone had astonishingly given way to healthy, functional bone. "We had hoped for a general increase in bone health. But the huge surprise was to find that the exquisite inner "coral-like" architecture of the bone structure of the injected animals - which is severely compromised in osteoporosis - was restored to normal."

The study could soon give rise to a whole new paradigm for treating or even indefinitely postponing the onset of osteoporosis. While there are no human stem cell trials looking at a systemic treatment for osteoporosis, the long-range results of the study point to the possibility that as little as one dose of stem cells might offer long-term relief. "It's very exciting. We're currently conducting ancillary trials with a research group in the U.S., where elderly patients have been injected with MSCs to study various outcomes. We'll be able to look at those blood samples for biological markers of bone growth and bone reabsorption." If improvements to bone health are observed in these ancillary trials, larger dedicated trials could follow within the next 5 years.

Friday, March 18, 2016

This is an intriguing study in mice in which researchers explore exactly which structures must be regrown and recovered in the brain in order to restore access to memories lost to the progression of Alzheimer's disease - or, indeed, any other form of neurodegeneration. It is a great example of the growing level of control over fine neural structures in living individuals that is made possible by the latest biotechnologies and an increased understanding of the biochemical basis for memory.

Loss of long-term memory for specific learned experiences is a hallmark of early Alzheimer's disease (AD) that is also exhibited by mice genetically engineered to develop AD-like symptoms. Building on their previous work that identified and activated memory cells, researchers have now shown that spines - small knobs on brain-cell dendrites through which synaptic connections are formed - are essential for memory retrieval in these AD mice. Moreover, fiber-optic light stimulation can re-grow lost spines and help mice remember a previous experience.

Mouse memory is often inferred from learned behavior, in this case associating an unpleasant footshock with a particular cage. Remembering and expecting shocks causes mice to freeze in this enclosure but not in a neutral one. Compared with normal mice, AD mice exhibited amnesia and reduced freezing behavior, indicating progressive memory loss. The engrams, or memory traces, of this particular experience are known to be located in the dentate gyrus of the hippocampus, a key brain area for memory processing. During fear conditioning, researchers used a virus to deliver a gene into the dentate gyrus, which labeled active engram cells. This allowed researchers to visually identify the neurons that made up the engram for that specific fear memory. A second virus contained a gene making only these engram neurons sensitive to light. When the engram cells were reactivated with light in the AD mice, memory of the footshock experience became retrievable and freezing behavior was restored.

Memories restored with this method faded away within a day, and the researchers next sought to understand why this happens. They noted a reduction in the number of spines as the mice aged and their Alzheimer's disease progressed. Their waning memory for the fear training was also linked to a loss of these spines. Previous work had shown that spines grow when neurons undergo long-term potentiation, a persistent strengthening of synaptic connectivity that happens naturally in the brain but can also be artificially induced through stimulation. Through repeated stimulation with high-frequency bursts of light to the hippocampal memory circuit in AD mice, the team was able to boost the number of spines to levels indistinguishable from those in control mice. The freezing behavior in the trained task also returned and remained for up to six days. The implication is that restoring lost spines in the hippocampal circuit facilitated retrieval of the specific fear experience and its associated freezing behavior. Light stimulation did not boost the number of spines in normal mice or strengthen the fear memory, nor did indiscriminately shining light in the dentate gyrus result in any long-term memory improvement. Only the precise stimulation of engram cells was able to increase the number of spines and bring about the memory improvement in AD mice.


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